PT1931660E - Phenyl-[1,2,4]-oxadiazol-5-one derivatives with phenyl group, processes for their preparation and their use as pharmaceuticals - Google Patents

Description

DESCRIPTION OF THE PREFERRED EMBODIMENTS OF PHENYL- [1,2,4] -OXADIAZOL-5-ONA WITH PHENYL GROUP, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS DRUGS " The invention relates to phenyl-1,2,4-oxadiazol-5-one derivatives with phenyl group and to their physiologically acceptable salts and physiologically functional derivatives which exhibit PPARdelta agonist activity.

PPARdelta agonists have been described in the prior art (e.g., WO 01/00603, WO 02/092590, WO 2004/080943, WO 2005/054213 and WO 2005/097786). Compounds comprising an oxadiazolone characteristic as factor Xa inhibitors have been disclosed in DE 10112768 A1, oral hypoglycemic agents in WO 96/13264. From WO 97/40017 are known compounds having a phenyl group attached to heterocycles as modulators of molecules with phosphotyrosine recognition units. Benzene derivatives as inhibitors of squalene synthase and protein-farnesyltransferase are described in W096 / 34851.

W02005 / 097762 and EP-A-1586573, which have publication dates prior to the date of presentation of the present invention, describe PPAR delta agonists, WO 2005/097762 those having a 1,2,4- oxadizol-3-one and EP-A-1586573 those having a linear bridging element. In US-A-5641796 oral hypoglycemic agents comprising an oxathiazolonthione group are disclosed. EP-A-1424330 and US-B1-6710063 disclose PPARdelta activators having a terminal carboxylic or tetrazole group. Kulkarni et al. (Bioorganic & Medicinal Chemistry, Elsevier Science Ltd., GB, 1999, 1475-1485) discloses antihyperglycemic agents having a terminal 2,4-thiazolidine-dione-methyl group.

Arylthiazolidinedione and aryloxazolidinedione derivatives are mentioned in WO 00/78313 and WO 96/13264 discloses oral hypoglycemic agents comprising a terminal oxadiazolone group directly attached to the neighboring phenyl / pyridyl group. The invention is based on the object of providing compounds which enable therapeutically usable modulation of lipid and / or carbohydrate metabolism and are thus suitable for the prevention and / or treatment of diseases such as type 2 diabetes and atherosclerosis and its various sequelae. Another object of the invention is to treat demyelinating disorders and other neurodegenerative disorders of the central and peripheral nervous systems.

A number of compounds have been found to modulate the activity of PPA receptors. The compounds are suitable, in particular, for activating PPARdelta and PPARalpha, however, it being possible to vary the degree of relative activation depending on the compounds.

The compounds of the present invention are: 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [ (2-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy-1,2,3,4-oxadiazol-5- ) -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- {3-methyl-1- [4-methyl-2- (4-trifluoromethyl-phenyl) - thiol-5-yl] -butoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl (2-chloro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} trifluoromethyl-phenyl) -thiazol-5-yl] -2-phenyl-ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4 - {[4- 2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -phenylmethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- { 1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -3-phenyl-propoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-5-yl] -3-phenyl-propoxy} -phenyl) -4H- [1,2,4- ] oxadiazol-5-one 3- (2-Chloro-4- {2- (4-fluoro-phenyl) -1- [4-methyl-2- (4-trifluoromethyl 1-yl) -ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- {1- [4- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -2-pyridin-2-yl-ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Bromo- 4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- [4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2-trifluoro-ethoxymethyl) -phenyl] -4H- [1,2,4] oxadiazol-5-one 3- (2-Methoxymethyl-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy] 3- (2-Ethoxymethyl-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-yl] -propoxy} 1-yl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Ethyl-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl ] propoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Cyclopropyl-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) 5-yl] -propoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol- 5-yl] propoxy} -naphthalen-1-yl) -4H- [1,2,4] oxadiazol-5-one 3- (4- {1- [4-Methyl- trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2-trifluoromethylphenyl) -4H- [1,2,4] oxadiazol-5-one 3- (4'-Fluoro-5- {1- [4- methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -biphenyl-2-yl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro- 4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- {2,2-difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -butoxy} (2-Fluoro-4- (2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) thiazol-5-yl] ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- (2,2,2-trifluoro- 2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Cyclopropyl-4- { 2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5 3- (8- (2,2,2-Trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -quinolin-5-yl) - 4H- [1,2,4] oxadiazol-5-one 3- (4- {2,2,2-Trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -naphthalen-1-yl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Fluoro- 2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (4- {4- - [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxymethyl} -naphthalen-1-yl) -4H- [1,2,4] oxadiazol-5-one 3- ( 4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- ( 4- (2,2-Difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -butoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol- 5- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) -4H- - [1,2,4] oxadiazol-5-one 5- (4- {2- (4-Difluoromethyl-phenyl) -2,2-difluoro-1- [4-methyl-2- (4-trifluoromethyl- phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Fluoro-4- {2- [4-methyl- 4- (1-methyl-4-trifluoromethyl-phenyl) -thiazol-5-yl] -hexyl} -phenyl) -4H- [1,2,4] oxadiazol- -2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl} yl) -4H-1,2,4-oxadiazol-5-one 3- (2-Fluoro-4 - {(R) -1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl- piperidin-1-ylmethyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2-Difluoromethoxy-4- {1- [4- 2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2-Methoxy-4- {1- [4- 2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2-Methoxy-4 - {( R) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2- 4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one - (5-Fluoro-2-methoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4 3- (5-Fluoro-2-methoxy-4 - {(R) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} 3- (2-Difluoromethoxy-5-fluoro-4 - {(R) -1- [4-methyl-2- (4-trifluoromethyl- phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2-Methoxy- - [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5 2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -amide propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2- (2,2,2-Trifluoro-ethoxy) -4- {1- [2- (4-trifluoromethyl-phenyl ) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2-Difluoromethoxy- {1- [2- (4-Trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazole -5-one 3- (2-Difluoromethoxy-4 - {(R) -1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl ] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2-Difluoromethoxy-5-fluoro-4- {1- [2- (4-trifluoromethyl-phenyl) -4- 4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- [5-Fluoro-4- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2-trifluoro-ethoxy) -phenyl] -4H- 1,2,4-oxadiazol-5-one 3- [4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- 3- [4 - {(R) -1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -piperazin- ) -thiazol-5-yl] -propoxy} -2- (2,2,2-trifluoro-ethoxy) -phenyl] -4H-1,2,4-oxadiazol-5-one 3- (5-Fluoro-2- - (2,2,2-trifluoro-ethoxy) -4- {1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] - propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one

This invention also encompasses all combinations of preferred aspects of the invention described herein.

The optically active carbon atoms present in the compounds of the formula I may independently have the R configuration or the S configuration. The compounds of the formula I may be present in the form of pure enantiomers or pure diastereomers or in the form of mixtures of enantiomers and / or diastereomers, for example in the form of racemates. The present invention relates to pure enantiomers and mixtures of enantiomers as well as to pure diastereomers and mixtures of diastereomers. The invention comprises mixtures of two or more of two stereoisomers of the formula I and comprises all proportions of the stereoisomers in the mixtures. In the case where the compounds of formula I may be present as E-isomers or Z-isomers (or cis isomers or trans isomers) the invention relates to pure E isomers and pure Z isomers and to E / Z blends in all proportions. The invention also comprises all tautomeric forms of the compounds of formula I.

Diastereomers, including E / Z isomers, may be separated into the individual isomers, for example by chromatography. The racemates can be separated into the two enantiomers by standard methods, for example chromatography on chiral phases or by resolution, for example by crystallization of diastereomeric salts obtained with optically active acids or bases. Stereochemically uniform formula I compounds can also be obtained using stereochemically uniform starting materials or using stereoselective reactions.

The compounds of formula I may exist in the form of their racemates, racemic mixtures, pure enantiomers, diastereomers and mixtures of diastereomers as well as in their tautomeric forms. The present invention encompasses all of these isomeric and tautomeric forms of the compounds of formula I. These isomeric forms can be obtained by known methods, even if not specifically described in some cases. Because their solubility in water is greater than that of the starting or basic compounds, the pharmaceutically acceptable salts are particularly suitable for medical applications. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are the salts of inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable pharmaceutically acceptable basic salts are the ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), and salts of trometamol (2- amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion, such as, for example, trifluoroacetate, also belong to the context of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic applications, for example in vitro. The term " physiologically functional derivative " used herein refers to any physiologically tolerated derivative of a compound of the formula I of the invention, for example an ester, which when administered to a mammal, such as, for example, a human is capable of forming (directly or indirectly) a compound of the formula I or an active metabolite thereof.

Physiologically functional derivatives also include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo into a compound of the invention. These prodrugs may be by themselves active or not.

The compounds of the invention may also exist in various polymorphic forms, for example as crystalline and amorphous polymorphic forms. All polymorphic forms of the compounds of the invention belong to the context of the invention and are a further aspect of the invention. 10

All references to " compound (s) of formula I " below refer to the compound (s) of formula I as described above, and the physiologically functional salts, solvates and derivatives thereof as described herein.

Use

This invention further relates to the use of compounds of formula I and their pharmaceutical compositions as PPAR ligands. The PPAR ligands of the invention are suitable as modulators of PPAR activity.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that can be activated by ligands and belong to the class of nuclear hormone receptors. There are three isoforms of PPAR, PPARalpha, PPARgamma and PPARdelta (identical to PPARbeta), which are encoded by different genes (Peroxisome proliferator-activated receptor (PPAR): structure, mechanisms of activation and diverse functions: Motojima K., Cell Struct Funct 1993, 18 (5), 267-77).

In humans, PPARgamma exists in three variants, PPARgamma, gamma2 and gamma3, which are the result of the alternative use of promoters and the differential excision-junction of mRNA. The different PPARs have different tissue distribution and modulate different physiological functions. PPARs play a key role in various aspects of the regulation of a large number of genes whose products are directly or indirectly crucially involved in the metabolism of lipids and carbohydrates. Thus, for example, the PPARalpha receptor plays an important role in the regulation of fatty acid catabolism or lipoprotein metabolism in the liver, while PPARγα is crucially involved, for example, in the regulation of adipose cell differentiation. However, in addition, PPARs are also involved in the regulation of many other physiological processes, including those not directly related to the metabolism of carbohydrates or lipids. The activity of the different PPARs can be modulated by various fatty acids, fatty acid derivatives and synthetic compounds to varying degrees. For relevant reviews on functions, physiological effects and pathophysiology, see: Berger, J. et al. , Annu. Rev. Med., 2002, 53, 409-435; Wilson, T. et al. , J. Med. Chem., 2000, 43 (4), 527-550; Kliewer, s. et al. , Recent Prog. Horm Res., 2001, 56, 239-63; Moller, D.E. and Berger, J.P., Int J Obes Relat Metab Disord., 2003, 27 Suppl 3, 17-21; Ram, V.J., Drugs Today, 2003, 39 (8), 609-32).

Of the three PPAR isoforms, the physiological functions of PPARdelta have long remained an enigma. The first pharmacological role proposed for PPARdelta was the regulation of cholesterol homeostasis. Some selective ligand of PPARdelta L-165041 has been shown to increase plasma cholesterol in a diabetic animal model (Berger J. et al., J. Biol. Chem., 1999, 274, 6718-6725; Leibowitz MD, et al. FEBS Lett., 2000, 473 (3), 333-336). In rhesus monkeys

obese, insulin-resistant, potent and selective ligand of PPARdelta GW501516 increases HDL cholesterol, decreases plasma LDL, triglyceride and insulin levels (Oliver, W. et al., Proc. Natl. , 98, 5306-5361). The PPARdelta / PPARalpha YM-16638 double agonist significantly reduces plasma lipids in rhesus and cynomolgus monkeys (Goto, S. et al., Br. J. Pharm., 1996, 118, 174-178) and acts in a manner similar in two-week clinical trials in healthy volunteers (Shimokawa, T. et al., Drug Dev. Res., 1996, 38, 86-92).

More recent publications have pointed out that PPARdelta is an important target for the treatment of dyslipidemia, insulin resistance, type 2 diabetes, atherosclerosis and X syndrome (Wang, YX et al., Cell, 2003, 113, 159-170; , S., et al., FASEB J., 2003, 17, 209-226, Tanaka, T. et al., PNAS, 2003, 100, 15924-15929, Holst, D. et al., BioChem Biophys. , 2003, 1633, 43-50; Dressel, U. et al., Mol. Endocrin., 2003, 17, 2477-2493, Lee, C.H. et al., Science, 2003, 302, 453-457 ).

In addition to its actions as a regulator of lipid, glucose and cholesterol metabolism, PPARdelta is known to play a role in embryonic development, implantation and bone formation (Lim, H. and Dey, SK, Trends Endocrinol Metab., 2000, 11 (4), 13-42; Ding, NZ et al., Mol Reprod Dev., 2003, 66 (3), 218-24; Mano, H. et al., J Biol Chem., 2000, 275 11), 8126-32).

Numerous publications demonstrate that PPARdelta triggers the proliferation and differentiation of keratinocytes, which points to their role in skin disorders and wound healing (Di-Poi, N. et al., J Steroid Biochem Mol Biol., 2003, 85 (2-5), 257-65; Tan, NS et al., Am J Clin

Dermatol., 2003, 4 (8), 523-30; Wahli, W., Swiss Med Wkly., 2002, 132 (7-8), 83-91). PPARdelta appears to be significantly expressed in the CNS; however, much of its function remains to be identified. However of exceptional interest is the identification that PPARdelta was expressed in the oligodendrocytes, the major CNS lipid producing cells, of rodents (J. Granneman, et al., J. Neurosci. Res., 1998, 51, 563- 573).

Furthermore, a PPARdelta selective agonist has also been found to significantly increase oligodendroglial myelin gene expression and myelin coating diameter in mouse cultures (I. Saluja et al., Glia, 2001, 33, 194-204) . Thus, PPARdelta activators may be useful for the treatment of demyelinating and dysmyelinating diseases. The use of delta peroxisome proliferator-activated receptor agonists for the treatment of MS and other demyelinating diseases can be shown as described in WO2005 / 097098.

Demyelinating conditions are manifested by loss of myelin - the multiple dense layers of lipids and proteins that cover many nerve fibers. These layers are provided by oligodendroglia in the central nervous system (CNS) and by Schwann cells in the peripheral nervous system (PNS). In patients with demyelinating conditions, demyelination may be irreversible; this is usually accompanied or followed by axonal degeneration and often cell degeneration. Demyelination can occur as a consequence of neuronal damage or myelin damage - due to aberrant immunological responses, local injury, ischemia, metabolic disorders, toxic agents or viral infections (Prineas and McDonald, Demyelinating Diseases, In Greenfield's

Neuropathology, 6th edition suppl. (Edward Arnold: New York, 1997) 813-811, Beers and Berkow, eds., The Merck Manual of

Diagnosis and Therapy, 17th edition suppl. (Whitehouse Station, N.J., Merck Research Laboratories, 1999) 1299, 1437, 1473-76, 14-1463). Central demyelination (CNS demyelination) occurs in several states, often of uncertain etiology, which have become known as primary demyelinating diseases. Of these, multiple sclerosis (MS) is the most prevalent. Other primary demyelinating diseases include adrenoleukodystrophy (ALD), adrenomyeloneuropathy, AIDS-associated vacuolar myelopathy, HTLV-associated myelopathy, Leber's hereditary optic atrophy, progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis, Guillian-Barre syndrome, and tropical spastic paraparesis. In addition, there are acute states in which CNS demyelination may occur, e.g. acute disseminated encephalomyelitis (ADEM) and acute viral encephalitis. In addition, acute transverse myelitis, a syndrome in which an acute transection of the spinal cord of unknown cause affects gray and white matter in one or more adjacent thoracic segments, may also result in demyelination. Likewise, disorders in which myelin-forming glial cells, including spinal cord injuries, neuropathies, and nerve fiber injury, are damaged. The present invention relates to compounds of formula I suitable for modulating PPAR activity, especially PPARdelta and PPARalpha activity. Depending on the modulation profile, the compounds of formula I are suitable for the treatment, control and prophylaxis of the indications described below and for a number of other pharmaceutical applications related thereto (see, for example, Berger, J., et al. , Et al., J. Med. Chem., 2000, 43 (4), 527-550, Kliewer, S. et al. , Recent

Prog Horm Res., 2001, 56, 239-63; Fruchart, J. C. et al., 2001, Pharmacological Research, 44 (5), 345-52; Kersten, S. et al., 15

Curr Opin I.P. et al.

Nature, 2000, 405, 421-424; Burn,

Lipidol, 2001, 12, 245-254).

Compounds of this type are particularly suitable for the treatment and / or prevention of: 1. Disorders of fatty acid metabolism and disorders of use of glucose.

Disturbances in which insulin resistance is involved 2. Diabetes mellitus, especially type 2 diabetes, including the prevention of associated sequelae.

Particular aspects in this regard are hyperglycemia, improved insulin resistance, improved glucose tolerance, pancreatic β-cell protection, prevention of macro- and microvascular disorders 3. Dyslipidemias and their sequelae, such as, for example, atherosclerosis, coronary disease, cerebrovascular disorders etc., especially those (but not limited to) which are characterized by one or more of the following factors: high plasma triglyceride concentrations, high post-prandial plasma triglyceride concentrations,

low concentrations of HDL cholesterol low concentrations of apoL lipoprotein high concentrations of LDL cholesterol small particles of LDL cholesterol high concentrations of ApoB lipoprotein 4. Several other conditions that may be associated with metabolic syndrome, such as: obesity (overweight), including central hypertrophic thrombosis, hypercoagulability, and prothrombotic (arterial and venous) conditions elevated blood pressure heart failure, such as, but not limited to, myocardial infarction, hypertensive heart disease or cardiomyopathy 5. Disorders or conditions in which inflammatory reactions are involved: atherosclerosis, such as, for example (but not limited to), coronary sclerosis including angina pectoris or myocardial infarction, stroke restenosis or vascular reocclusion chronic inflammatory bowel diseases such as , for example, doe Crohn's disease and ulcerative colitis asthma lupus erythematosus (LE) or inflammatory rheumatic disorders, such as, for example, rheumatoid arthritis, other inflammatory conditions 17 6. Disorders of the cell cycle or processes of cell differentiation: adipose cell tumors, lipomatous carcinomas, such such as, for example, liposarcomas solid tumors and neoplasms, such as, for example (but not limited to) carcinomas of the gastrointestinal tract, liver, bile duct and pancreas, endocrine tumors, carcinomas of the lungs, kidneys and urinary tract, genital tract, prostate carcinomas, etc. acute and chronic myeloproliferative disorders and lymphangio angiogenesis 7. Demyelinating disorders and other neurodegenerative disorders of the central and peripheral nervous systems including: Alzheimer's disease - multiple sclerosis - Parkinson's disease adrenoleukodystrophy (ALD) adrenomyeloneuropathy - AIDS-associated vacuolar myelopathy HTLV-associated myelopathy atrophy Leber's hereditary optic leukoencephalopathy (PML) subacute sclerosing panencephalitis Guillian-Barre Syndrome 18 tropical spastic paraparesis acute disseminated encephalomyelitis (ADEM) acute viral encephalitis acute transverse myelitis traumatic brain and spinal cord Charcot-Marie-Tooth disease 8 Skin disorders and / or disorders of wound healing processes: erythematous-squamous dermatoses such as, for example, psoriasis acne vulgaris other skin disorders and dermatological conditions that are modulated by PPAR eczemas and neurodermatitis dermatitis, such as, for example, seborrheic dermatitis or photodermatitis keratitis and keratoses, such as, for example, seborrheic keratoses, senile keratoses, actinic keratosis, photoinduced keratoses or keloid follicular keratosis and prophylaxis of keloid - warts, including condylomata or condylomata acuminata by human papilloma virus (HPV), such as, for example, venereal papilloma, viral warts, such as, for example, contagious molluscum, papular leukoplakia, such as, for example, flat lichen

skin cancer, such as, for example, basal cell carcinomas, cutaneous melanoma or T-cell lymphomas 19 Localized benign epidermal tumors, such as, for example, keratoderma, epidermal nevi - wounds healing wounds 9. Other disorders elevated blood pressure pancreatitis

polycystic ovarian syndrome (PCOS) asthma osteoarthritis lupus erythematosus (LE) or inflammatory rheumatic disorders such as, for example, rheumatoid arthritis vasculitis loss of mass (cachexia) gout ischemia / reperfusion syndrome acute respiratory failure syndrome (ARDS)

Formulations The amount of a compound of formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range of from 0.001 mg to 100 mg (typically from 0.01 mg to 50 mg) per day per kilogram of body weight, for example 0.1-10 mg / kg / day. An intravenous dose may be, for example, in the range of from 0.001 mg to 1.0 mg / kg, which may suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. The single doses may contain, for example, from 1 mg to 10 g of the active ingredient. Thus, ampoules for injection may contain, for example, from 1 mg to 100 mg, and single dose formulations which can be administered orally, such as, for example, capsules or tablets, may contain, for example, from 0.05 to 1000 mg, typically from 0.5 to 600 mg. For the therapy of the above conditions, the compounds of formula I may be used as the compound itself, but these are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must of course be acceptable in the sense that it is compatible with the other ingredients of the composition and is not detrimental to the health of the patient. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the ingredient active. Other pharmaceutically active substances, including other compounds of formula I, may also be present. The pharmaceutical compositions of the invention may be produced by one of the known pharmaceutical methods, which consists essentially of mixing the ingredients with pharmacologically acceptable carriers and / or excipients.

The pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (e.g., sublingual) and parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends, in each case in particular, the nature and severity of the condition being treated and the nature of the compound of formula I used in each case. The coated formulations and coated slow release formulations also belong to the context of the invention. Preference is given to formulations resistant to acid and to gastric juice. Suitable gastric juice resistant coatings comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Pharmaceutical preparations suitable for oral administration may be in the form of separate units, such as, for example, capsules, cachets, lozenges or tablets, each containing a defined amount of the compound of formula I; as powders or granulates, as solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions may be prepared by any suitable pharmaceutical method, which comprises a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. The compositions are generally produced by uniformly and homogeneously mixing the active ingredient with a finely divided liquid and / or solid carrier, whereupon the product is molded, if necessary. Thus, for example, a tablet may be produced by pressing or shaping a powder or granulate of the compound, where appropriate with one or more additional ingredients. Compressed tablets may be produced by tabletting the compound in loose form, such as, for example, a powder or granulate, where appropriate mixed with a binder, glidant, inert diluent and / or one (or more) surfactant / dispersant ) on a suitable machine. The molded tablets may be produced by molding the compound, which is in powder form and moistened with an inert liquid diluent, into a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise tablets for sucking, which contain a compound of formula I with a flavoring, usually sucrose and gum arabic or tragacanth, and tablets comprising the compound on an inert base, such as gelatin and glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also occur by subcutaneous, intramuscular or intradermal injection. These preparations may preferably be produced by mixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.

Pharmaceutical compositions suitable for rectal administration are preferably in the form of single dose suppositories. These may be made by mixing a compound of formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting blend.

Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. The vehicles which may be used are petroleum jelly, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%. Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses may be in the form of individual patches which are suitable for prolonged intimate contact with the epidermis of the patient. Such patches suitably contain the active ingredient in an aqueous solution which is buffered, where appropriate, dissolved and / or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%. A particular possibility is that the active ingredient is released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 368 (1986).

The compounds of formula I are distinguished by favorable effects on metabolic disorders. These beneficially influence the metabolism of lipids and sugars, in particular these reduce the level of triglycerides and are suitable for the prevention and treatment of type II diabetes and atherosclerosis and their various sequelae. 24

Associations with other medicinal products

The compounds of the invention may be administered alone or in combination with one or more other pharmacologically active substances. In particular, the compounds of the invention may be administered in combination with active ingredients having a similar pharmacological action. For example, these may be administered in combination with active ingredients that have favorable effects on metabolic disorders or disorders often associated therewith. Examples of such medicaments are: 1. blood glucose lowering drugs, antidiabetics, 2. active ingredients for the treatment of dyslipidemias, 3. antiatherosclerotic medicines, 4. anti-obesity agents, 5. anti-inflammatory active ingredients 6. active ingredients for the treatment of malignant tumors 7. active antithrombotic active ingredients 8. active ingredients for the treatment of elevated blood pressure 9. active ingredients for the treatment of heart failure and 10. active ingredients for the treatment and / or prevention of complications caused by diabetes or associated to diabetes. 11. active ingredients for the treatment of neurodegenerative diseases 12. active ingredients for the treatment of disorders of the central nervous system 13. active ingredients for the treatment of drug, nicotine and alcohol dependence 14. analgesics

These may be combined with the compounds of the invention of the formula I in particular for a synergistic improvement of the activity. Administration of the active ingredient combination may occur by separate administration of the active ingredients to the patient or in the form of combination products in the bladders a multiplicity of active ingredients is present in a pharmaceutical preparation.

Other particularly active ingredients suitable for combination preparations are:

All antidiabetics mentioned in Rote Liste 2006, Chapter 12; all the slimming agents / appetite suppressants mentioned in the Rote Liste 2006, Chapter 1; all of the lipid-lowering agents mentioned in Rote Liste 2006, Chapter 58. These may be combined with the compound of the formula I according to the invention in particular for a synergistic improvement of the activity. The combination of active compound may be administered by separate administration of the active compounds to the patient or in the form of combination preparations in which a multiplicity of active compounds is present in a pharmaceutical preparation. Most of the active compounds listed below are disclosed in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.

Antidiabetics include insulin and insulin derivatives, such as, for example, Lantus® (see www.lantus.com) or HMR 1964 or those described in WO 2005005477 (Novo Nordisk), fast acting insulins (see US 6, 221, 633 ), inhalable insulins, such as, for example, Exubera® or oral insulins, such as, for example, IN-105 (Nobex) or Oral-lyn ™ (Generex

Biotechnology), GLP-1 derivatives, such as, for example, Exenatide, Liraglutide or those disclosed in WO 98/08871 or W02005027978 to Novo Nordisk A / S, WO 01/04156 to Zealand or WO 00 / 34331 of Beaufour-Ipsen, pramlintide acetate (Symlin; Amylin Pharmaceuticals) and also orally effective hypoglycemic active ingredients.

Preferably the active compounds include sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glycogen phosphorylase inhibitors, glucagon antagonists, glucokinase activators, fructose 1,6-bisphosphatase inhibitors, transporter modulators (GLUT4) inhibitors, glutamine: fructose-6-phosphate amidotransferase (GFAT) inhibitors, GLP-1 agonists, potassium channel openers, such as, for example, those disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A / S, dipeptidylpeptidase IV (DPP-IV) inhibitors, insulin sensitizers, liver enzyme inhibitors involved in the stimulation of gluconeogenesis and / or glycogenolysis, glucose uptake modulators, glucose transport and glucose reuptake inhibitors, β-HSD1 inhibitors, protein tyrosine phosphatase inhibitors 1B (PTP1B), sodium / glucose co-transporter modulators 1 or 2 (SGLT1, SG LT2), lipid metabolism altering compounds, such as antihyperlipidemic active ingredients and antitilipidemic active ingredients, compounds that reduce food intake or food absorption, thermogenic enhancing compounds, PPAR and RXR modulators, and ingredients active agents acting on the ATP-dependent potassium channel of the beta cells.

In one embodiment of the invention, the compound of formula I is administered in combination with an HMGCoA reductase inhibitor, such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin or L-659699. In one embodiment of the invention, the compound of formula I is administered in combination with a cholesterol reuptake inhibitor such as, for example, ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol / campesterol ascorbyl phosphate; Forbes Medi- Tech., WO 292005021497) W02005062824 W02005061452 W02005042692), MD-0727 (Microbial Inc., document or with compounds as described in the document (Kotobuki Pharmaceutical Co. Ltd.), document (Merck & Co.) or W02005061451 and AstraZeneca AB) from PPARone,

In one embodiment of the invention, the compound is administered in combination with an agonist such as, for example, rosiglitazone, pioglitaz 262570, R-483 or CS-011 (rivoglitazone).

In one embodiment of the invention, the compound of formula I is administered in combination with a PPAR alpha agonist such as, for example, GW9578, GW-590735, K-111, LY-674, KRP-101 or DRF-1 0945.

In one embodiment of the invention, the compound of formula I is administered in combination with a mixed PPAR alpha / gamma agonist such as, for example, muraglitazar, tesaglitazar, Naveglitazar, LY-510929, ONO-5129, E-3030 or as described in WOOO / 64888, WOOO / 64876, W003 / 020269, W02004075891, W02004076402, W02004075815, W02004076447, W02 04076428, W02004076401, W02004076426, W02004076427, W02006018118, W02006018115 and W02006018116 or JP Berger et al., TRENDS in Pharmacological Sciences 28 (5), 244-251, 2005.

In one embodiment of the invention, the compound of formula I is administered in combination with a delta PPAR agonist, such as, for example, GW-501516 or as described in WO2005097762, WO2005097786, WO2005097763 and WO2006029699. 30

In one embodiment of the invention, the compound of formula I is administered in combination with metaglidasen or MBX-2044 or other PPAR gamma partial agonists / antagonists.

In one embodiment of the invention, the compound of formula I is administered in combination with a fibrate, such as, for example, fenofibrate, clofibrate or bezafibrate.

In one embodiment of the invention, the compound of formula I is administered in combination with an MTP inhibitor, such as, for example, imipaptide, BMS-201038, R-103757 or those described in WO2005085226.

In one embodiment of the invention, the compound of formula I is administered in combination with a CETP inhibitor, such as, for example, torcetrapib or JTT-705.

In one embodiment of the invention, the compound of formula I is administered in combination with a bile acid reuptake inhibitor (see, for example, US 6245744, US 6221897 or WOOO / 61568), such as, for example, HMR 1741 or those described in DE 102005033099.1 and DE 102005033100.9.

In one embodiment of the invention, the compound of formula I is administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine or colesevelam.

In one embodiment of the invention, the compound is administered in association with an LDL receptor (see US 6342512) inducer, such as, for example, HMR1171, HMR1586 or those described in WO2005097738.

In one embodiment, the compound of formula I is administered in combination with Omacor® (omega-3 fatty acids, highly concentrated eicosapentaenoic acid and docosahexaenoic acid esters).

In one embodiment of the invention, the compound of formula I is administered in combination with an ACAT inhibitor, such as, for example, avasimib.

In one embodiment of the invention, the compound of formula I is administered in combination with an antioxidant, such as, for example, OPC-14117, probucol, tocopherol, ascorbic acid, β-carotene or selenium.

In one embodiment of the invention, the compound of formula I is administered in combination with a vitamin, such as, for example, vitamin B6 or vitamin B12.

In one embodiment of the invention, the compound of formula I is administered in combination with a lipoprotein lipase modulator, such as, for example, ibrolipim (NO-1886).

In one embodiment of the invention, the compound of formula I is administered in combination with an ATP-citrate lyase inhibitor, such as, for example, SB-204990.

In one embodiment of the invention, the compound of formula I is administered in combination with a squalene synthetase inhibitor such as, for example, BMS-188494 or as described in WO2005077907.

In one embodiment of the invention, the compound of formula I is administered in combination with a lipoprotein antagonist (a), such as, for example, gemcaben (Cl-1027).

In one embodiment of the invention, the compound of formula I is administered in combination with an HM74A receptor agonist, such as, for example, nicotinic acid. compound of the cetylisteride inhibitor

In one embodiment of the invention, the formula I is administered in combination with a lipase, such as, for example, orlistat or (ATL-962).

In one embodiment of the invention, the formula I is administered in association with insulin. compound of the

In one embodiment of the invention, the compound of formula I is administered in combination with a sulfonylurea, such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.

In one embodiment of the invention, the compound of formula I is administered in combination with a biguanide, such as, for example, metformin.

In another embodiment of the invention, the compound of formula I is administered in combination with a meglitinide, such as, for example, repaglinide or nateglinide. 33

In one embodiment of the invention, the compound of formula I is administered in combination with a thiazolidinedione, such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 to Dr. Reddy's Research Foundation, in particular 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy] phenyl] methyl] -2,4-thiazolidinedione.

In one embodiment of the invention, the compound of formula I is administered in combination with an Î ± -glucosidase inhibitor, such as, for example, miglitol or acarbose.

In one embodiment of the invention, the compound of formula I is administered in combination with an active ingredient that acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment of the invention the compound of formula I is administered in combination with more than one of the above-mentioned compounds, for example in association with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.

In one embodiment of the invention, the compound of formula I is administered in combination with a glycogen phosphorylase inhibitor, such as, for example, PSN-357 or FR-258900 or those described in WO2003084922, WO2004007455, WO2005073229-31 or WO2005067932. 34

In one embodiment of the invention, the compound of formula I is administered in combination with glucagon receptor antagonists, such as, for example, A-770077, NNC-25-2504 or, as in WO2004100875 or WO2005065680.

In one embodiment of the invention, the compound of formula I is administered in combination with glucokinase activators, such as, for example, RO-4389620, LY-2121260 (W02004063179), PSN-105, PSN-110, GKA-50 or those described, for example, by Prosidion in W02004072031, W02004072066, WO 05103021 or WO 06016178, by

Roche in WO 0058293, WO 00183465, WO 00183470, WO 00185706, WO 00185707, WO 01044216, GB 02385328, WO 02008209, WO 02014312, WO 0246173, WO 0248106, DE 10259786, WO 03095438, US 04067939 or WO 04052869, for Novo Nordisk in EP 1532980, WO 03055482, WO 04002481, WO 05049019, WO 05049019, WO 05066145 or WO 05123132, by Merck / Banyu in WO 03080585, WO03097824, WO04081001, WO05063738 or WO05090332, by Eli Lilly in WO 04063194, or by Astra Zeneca in WO 01020327, WO 03000262, WO 03/30267, WO 03015774, WO 04045614, WO 04046139, WO 05044801, WO 05054200, WO 05054233, WO 05056530, WO 05080359, WO 05080360 or WO 05121110.

In one embodiment of the invention, the compound of formula I is administered in combination with a glyconeogenesis inhibitor, such as, for example, FR-225654.

In one embodiment of the invention, the compound of formula I is administered in combination with fructose-1,6-bisphosphatase inhibitors (FBPase), such as, for example, CS-917. 35

In one embodiment of the invention, the compound of formula I is administered in association with modulators of glucose transporter 4 (GLUT4), such as, for example, KST-48 (D.-O. Lee et al., J. Biol. -Forsch Drug Res. 54 (12), 835 (2004)).

In one embodiment of the invention, the compound of formula I is administered in combination with glutamine: fructose-6-phosphate amidotransferase (GFAT) inhibitors, as described, for example, in WO2004101528.

In one embodiment of the invention, the compound of formula I is administered in combination with dipeptidylpeptidase IV (DPP-IV) inhibitors such as, for example, vildagliptin (LAF-237), sitagliptin (MK-0431), saxagliptin BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200, GW-825964X or as described in W02003074500, WO2003106456, WO200450658, W02005058901, W02005012312 , PCT / EP2005 / 007821, PCT / EP2005 / 008005, PCT / EP2005 / 008002, PCT / EP2005 / 008004, PCT / EP2005 / 008283, DE 102005012874.2 or DE 102005012873.4.

In one embodiment of the invention, the compound of formula I is administered in combination with 11-beta-hydroxysteroid dehydrogenase-1 inhibitors (ΙΙβ-HSD1), such as, for example, W0200344000, W02004103980, W02003104208, W02004041264, BVT- or W0200190090-94 2733, W0200344009, WO2004112784, W02004106294, W02004037251, those described, WO200343999, WO2004112779, W02003065983, W02004011410, W02004056744, for example, in WO2004112782, W02004113310, W02003104207, WO2004033427, WO2004065351, W02004089367 36, W02004089380, W02004089470-71, W02004089896, W02005016877 or W02005097759.

In one embodiment of the invention, the compound of formula I is administered in combination with inhibitors of protein B tyrosine phosphatase 1 (PTP1B), as described, for example, in W0200119830-31, WO200117516, W02004506446, W02005012295, PCT / EP2005 / 005311, PCT / EP2 0 05/005321, PCT / EP2005 / 007151, PCT / EP2005 / or DE 102004060542.4.

In one embodiment of the invention, the compound of formula I is administered in combination with modulators of sodium / glucose co-transporter 1 or 2 (SGLT1, SGLT2), such as, for example, KGA-2727, T-1095 and SGL -0010 or as described, for example, in W02004007517, W0200452903, W0200452902, WO2005121161, W02005085237, JP2004359630 or the like. L. Handlon on Expert Opin. The R. Patents (2005) 15 (11), 1531-1540.

In one embodiment of the invention, the compound of formula I is administered in combination with hormone-sensitive lipase (HSL) inhibitors, such as those described, for example, in WO 01/17981, WOO1 / 66531, WO2004035550, W02005073199 or W003 / 051842.

In one embodiment of the invention, the compound of the formula I is administered in combination with acetyl-CoA-carboxylase (ACC) inhibitors, such as those described, for example, in WO099946262 WO200372197, WO2003072197 or WO2005044814. 37

In one embodiment of the invention, the compound of formula I is administered in combination with a phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, such as those described, for example, in WO2004074288.

In one embodiment of the invention, the compound of formula I is administered in combination with a glycogen synthase kinase-3 beta inhibitor (GSK-3 beta), such as those described, for example, in US2005222220, WO0204046117, WO2005085230 , W02005111018, W02003078403, W02004022544. W02003106410, W02005058908, US2005038023, W02005009997, US2005026984, W02005000836, WO2004106343, EP1460075, W02004014910, W02003076442, W02005087727 or W02004046117.

In one embodiment of the invention, the compound of formula I is administered in combination with a beta-protein kinase C inhibitor (PKC beta), such as, for example, ruboxistaurin.

In one embodiment of the invention, the compound of formula I is administered in combination with an endothelin-A receptor antagonist, such as, for example, avosentan (SPP-301).

In one embodiment of the invention, the compound of formula I is administered in combination with " I-kappaB kinase " (IKK inhibitors), such as those described, for example, in W02001000610, W02001030774, W02004022553 or W02005097129. 38

In one embodiment of the invention, the compound of formula I is administered in combination with glucocorticoid receptor modulators as described, for example, in WO2005090336.

In another embodiment of the invention, the compound of formula I is administered in combination with CART modulators (see " Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice " Asakawa, A. et al. Hormone and Metabolic Research (2001), 33 (9), 554-558); NPY antagonists such as, for example, {4 - [(4-aminoquinazolin-2-ylamino) methyl] -cyclohexylmethyl} naphthalene-1-sulfonamide hydrochloride (CGP 71683A); peptide YY 3-36 (PYY 3-36) or analogous compounds, such as, for example, CJC-1682 (PYY3-36 conjugated to human serum albumin via Cys34), CJC-1643 (derived from PYY3-36 conjugating in vivo with serum albumin) or those described in WO2005080424; antagonists of the cannabinoid receptor 1, such as, for example, rimonabant, SR147778 or those described, for example, in EP 0656354, WO 00/15609, WO 02/076949, WO2005080345, WO2005080328, WO2005080343, WO0205075450, WO2005080357, 0 W02 0,170,700, W02003026647-48, W0200302776, W02003040107, W02003007887, W02003027069, US6509367, WO200132663, W02003086288, W02 0 0 03 8 7 037 W02004048317, WO2004058145, W02003084930, W02003084943, W02004058744, W02004013120, W02 0 04,029,204, W02004035566, W02004058249, WO2004058255, W02 0 04058727, W02004069838, US20040214837, US20040214855, US20040214856, W02004096209, W02 004096763, W02ΟΟ04 096794, W02004110453, US20050009870, WO2005016286, WO2005027837, WO2005077897; W02005008028, W02005008028, W0200500974, W02005007111, WO2005028456, W02004099157, W02004000817, W02 0 04111033-34, W02005007628, W02005063761-62, US20040266845, W02005000820, W0200411038-39, US20050054679, W02005061509 or MC4 agonists (for example [2- (3a- benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-chlorophenyl) -2- -oxoethyl] -1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxamide; or described in W02004078717, W02005051391, US20050164914 W02004005324, W02005030797, W02005000339, W02004072076, (WO 01/91752)) or LB53280, LB53279, THIQ, MB243, RY764, CHIR-785, PT-141 or those document W02005060985, W02005009950, W02004087159, W02004078716, W02004024720, WO2004112793, WOUS20050222014, US20050124636, US20050130988, WO2004037797, W02005042516, US20040224901, W0200501921, EP1460069, W02005047253, W02005047251, EP1538159, W02004072077 or W020 06 02 4390; (1-methyl-benzoxazol-6-yl) -3- [1,5] naphthyridin-4-ylurea hydrochloride (SB-334867-A) A) or those described, for example, in WO200196302, WO200185693, WO2004085403 or WO2005075458); histamine H3 receptor agonists (for example, oxalic acid salt of 3-cyclohexyl-1- (4,4-dimethyl-1,4,6,7-tetrahydroimidazo [4,5-c] pyridin- 5-yl) -propan-1-one (WO 00/63208) or those described in WO200064884, WO2005082893); CRF antagonists (e.g. [2-methyl-9- (2,4,6-trimethylphenyl) -9H-1,3,9-triazafluoren-4-yl] dipropylamine (WO 00/66585)); CRF BP antagonists (for example urocortin); urocortin agonists; β-agonists (such as, for example, 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2,3-dimethyl-1H-indol-6-yloxy) ethylamino] ethanol hydrochloride (WO 01/83451)); MSH agonists (melanocyte stimulating hormone); MCH receptor antagonists (A-761 concentrating hormone, A-665798, those compounds W02005085200, W02003015769, W02 06018280, W02002006245, melanin) (such as, for example, NBI-845, A-7989, ATC- 0175, T-226296, T-71, GW-803430 or described in WO2003 / 15769, W02 005019240, W02004011438, W02004012648, W02 004072025, W02005070898, W02005070925, W02006018279, W02004039780, W02003033476, W02002002744, W02003004027 or FR2868780); CCK-A agonists (such as, for example, {2- [4- (4-chloro-2,5-dimethoxyphenyl) -5- (2-cyclohexylethyl) -thiazol-2- ylcarbamoyl] -5,7-dimethylindol-1-yl] acetic acid (WO 99/15525), SR-146131 (WO 0244150) or SSR-125180); serotonin reuptake inhibitors (eg dexfenfluramine); Mixed serotonergic and noradrenergic compounds (for example, WO 00/71549); 5-HT receptor agonists, for example 1- (3-ethylbenzofuran-7-yl) piperazine oxalic acid salt (WO 01/09111); 5-HT 2C receptor agonists (such as, for example, APD-356, BVT-933 or those described in W0200077010, W020077001-02, W02005019180, WO2003064423, W0200242304 or W02005082859); 5-HT6 receptor antagonists, as described, for example, in WO2005058858; bombesin receptor agonists (BRS-3 agonists); galanin receptor antagonists; growth hormone (for example, human growth hormone or AOD-9604); growth hormone releasing compounds (tert-butyl 6-benzyloxy-1- (2-diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylate (WO 01/85695)); growth hormone secretagogue receptor antagonists (ghrelin antagonists), such as, for example, A-778193 or those described in WO2005030734; TRH agonists (see, for example, EP 0462884); Modulators of the decoupling protein 2 or 3; leptin agonists (see, for example, Lee, Daniel W., Leinung, Matthew C., Rozhavskaya-Arena, Marina, Grasso, Patricia, Leptin agonists as a potential approach to the treatment of obesity, Drugs of the Future (2001) , 26 (9), 873-881); DA agonists (bromocriptine or Doprexin); lipase / amylase inhibitors (as described, for example, in WO 00/40569); diacylglycerol O-acyltransferases (DGAT) inhibitors, as described, for example, in US2004 / 0224997, W02004094618, W0200058491, W02005044250, W02005072740, JP2005206492 or W02005013907; fatty acid synthase (FAS) inhibitors, such as, for example, C75 or those described in WO2004005277; oxintomodulin; oleoyl estrone or thyroid hormone receptor agonists such as, for example, KB-2115 or those described in WO20058279, WO200172692, WO200194293, WO2003084915, WO2004018421 or WO2005092316.

In one embodiment of the invention, the other active ingredient is leptin; 43

See, for example " Perspectives in the therapeutic use of leptin ", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gemma, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622.

In one embodiment of the invention, the other active ingredient is dexamphetamine or amphetamine.

In one embodiment of the invention, the other active ingredient is fenfluramine or dexfenfluramine.

In another embodiment of the invention, the other active ingredient is sibutramine.

In one embodiment of the invention, the other active ingredient is mazindol or phentermine.

In one embodiment, the compounds of formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, acrobat / Caromax® (Zunft HJ et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001

Sep-Oct), 18 (5), 230-6). Caromax is a carotene containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hochst, 65926 Frankfurt / Main). The combination with Caromax® is possible in a preparation or by separate administration of compounds of formula I and Caromax®. In this regard, Caromax® may also be administered in the form of food products, such as, for example, in pastry products or sticks. 44

In one embodiment of the invention, the compound of formula I is administered in combination with PDE inhibitors (phosphodiesterase), as described, for example, in W02003 / 077949 or W02005012485.

In one embodiment of the invention, the compound of formula I is administered in combination with NAR-1 (nicotinic acid receptor) agonists as described, for example, in WO2004094429.

In one embodiment of the invention, the compound of formula I is administered in combination with CB2 (cannabinoid receptor) agonists as described, for example, in US2005 / 143448. The preferred embodiment of the invention is administered in association with WO2006017504.

In one embodiment formula I is administered in histamine 1 as described, W02005101979. In a disclosed Formula I of the invention, the agonist combination compound of, for example, the bupropion compound, as

In one embodiment of the invention, the compound of formula I is administered in combination with opioid antagonists as described, for example, in W02005107806 or W02004094429.

In one embodiment of the invention, the compound of formula I is administered in combination with neutral endopeptidase inhibitors as described, for example, in W0200202513, WO2002 / 06492 W02002047670. WO 2002040008 W02002040022 or

In one embodiment of the invention, the compound of formula I is administered in combination with NPY (neuropeptide Y) inhibitors as described, for example, in WO2002047670.

In one embodiment of the invention, the compound of formula I is administered in combination with sodium / hydrogen exchange inhibitors as described, for example, in WO2003092694.

In one embodiment of the invention, the compound of formula I is administered in combination with glucocorticoid receptor modulators as described, for example, in WO2005090336.

In one embodiment of the invention, the compound of formula I is administered in combination with nicotine receptor agonists as described, for example, in WO2004094429.

In one embodiment of the invention, the compound of formula I is administered in combination with NRI (norepinephrine reuptake inhibitors) as described, for example, in WO2002053140.

In one embodiment of the invention, the compound of formula I is administered in association with MOA (E-beta-methoxyacrylate), such as, for example, segelin, or as described, for example, in WO2002053140. 46

In one embodiment of the invention, the compound of formula I is administered in combination with active antithrombotic ingredients, such as, for example, clopidogrel. It is to be understood that each suitable association of the compounds according to the invention with one or more of the above-mentioned compounds and optionally one or more other pharmacologically active substances is intended to be within the scope of the present invention.

The formulas for some of the development codes mentioned above are given below.

4 7

ο LY-674

48

49

50

51

Cl

The activity of the compounds was tested as follows:

Determination of EC50 values of PPAR agonists in the PPARalpha cell assay

The potency of substances which bind to human PPARalpha and activate it in an agonist manner is analyzed using a stably transfected HEK (human embryonic kidney) HEK cell line which is referred to herein as PPARalpha reporter cell line . It contains two genetic elements, a luciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARalpha (GR-GAL4-PPARalpha-LBD) fusion protein that mediates expression of the luciferase reporter element depending on a ligand of PPARalpha. The humanly stable and constitutively expressed GR-GAL4-PPARalpha-LBD fusion protein binds to the cell nucleus of the PPARalpha reporter cell line through the portion of the GAL4 protein to the GAL4 DNA binding motifs at the 5 ' upstream of the luciferase reporter element that is stably integrated into the cell line genome. There is only poor expression of the luciferase reporter gene in the absence of a PPARalpha ligand if fetal calf serum depleted in fatty acids (cs-FCS) is used in the assay. The PPARalpha ligands bind to and activate the PPARalpha fusion protein and thereby stimulate expression of the luciferase reporter gene. The luciferase that is formed can be detected by chemiluminescence through an appropriate substrate.

Construction of the PPARalpha reporter cell line The PPARalpha reporter cell line was prepared in two steps. First, the luciferase reporter element was stably constructed and transfected into HEK cells. For this purpose, five yeast transcription factor binding sites GAL4 (Accession No. AF264724) were cloned at the 5 'position upstream of a minimum MMTV promoter at 68 bp in length (Accession No. V01175). The minimal MMTV promoter section contains a CCAAT box and a TATA element to allow efficient transcription by RNA polymerase II. Cloning and sequencing of the GAL4-MMTV construct occurred analogously to the description of Sambrook J. et al. (Molecular cloning, Cold Spring Harbor Laboratory Press, 1989). Then, the entire Photinus pyralis gene (Accession No. M15077) was cloned at the 3 'position downstream of the GAL4-MMTV element. After sequencing, the luciferase reporter element consisting of five GAL4 binding sites, MMTV promoter and luciferase gene was recloned into a zeocin resistance plasmid to obtain the plasmid pdeltaM-GAL4-Luc-Zeo. This vector was transfected into HEK cells according to reports in Ausubel, F. M. et al. (Current protocols in molecular biology, Vol. 1-3, John Wiley & Sons, Inc., 1995). Zeocin-containing medium (0.5 mg / ml) was then used to select a suitable stable cell clone which had a very low basal expression of the luciferase gene. 53

In a second step, the PPARalpha fusion protein (GR-GAL4-PPARalpha-LBD human was introduced into the described stable cell clone. For this purpose, initially the cDNA encoding the N-terminal 76 amino acids of the glucocorticoid receptor Access P04150) was ligated to the cDNA section encoding amino acids 1-147 of the yeast transcription factor GAL4 (Accession No. P04386). The cDNA of the human PPARalpha receptor ligand binding domain (amino acids S167-Y468; N (GR-GAL4-PPARalpha-LBD) was recloned on the plasmid pcDNA3 (Invitrogen) to allow for constitutive expression in the same cytomegalovirus promoter This plasmid was linearized with a restriction endonuclease and stably transfected into the above-described cell clone containing the luciferase reporter element The rep cell line terminus of PPARalpha reporter that contains a luciferase reporter element and constitutively expressed the PPARalpha fusion protein (GR-GAL4-PPARalpha-LBD) was isolated by selection with zeocin (0.5 mg / mL) and G418 (0.5 mg / mL).

Assay Procedure The activity of the PPARalpha agonists is determined in a 3 day assay, which is described below:

Day 1 of The PPARalpha reporter cell line is grown to 80% confluency in DMEM (No. 41965-039, Invitrogen) which is mixed with the following supplements: 10% cs-FCS (fetal calf serum; SH-30068.03, Hyclone), 0.5 mg / ml zeocin (No. R250-01, Invitrogen), 0.5 mg / ml G418 (No. 10136-027,

Invitrogen), 1% penicillin-streptomycin solution (No. 15140-122, Invitrogen) and 2 mM L-glutamine (No. 25030-024,

Invitrogen). The culture is carried out in standard cell culture flasks (No. 353612, Becton Dickinson) in a cell culture incubator at 37øC in the presence of 5% CO 2. The 80% Cofluente cells are washed once with 15 mL PBS (No. 14190-094, Invitrogen), treated with 3 mL trypsin solution (No. 25300-054, Invitrogen) at 37 ° C for 2 min, taken up in 5 mL of the described DMEM and counted in a cell counter. After dilution to 500,000 cells / mL, 35,000 cells are loaded into each well of a 96 well microtiter plate with a clear plastic base (No. 3610, Corning Costar). The plates are incubated in the cell culture incubator at 37øC and 5% CO 2 for 24 h.

Day 2

The PPARalpha agonists to be tested are dissolved in DMSO at a concentration of 10 mM. This stock solution is diluted in DMEM (No. 41965-039, Invitrogen) which is mixed with 5% cs-FCS (SH-30068,03, Hyclone), 2 mM L-glutamine (No. 25030-024 , Invitrogen) and the antibiotics previously described (zeocin, G418, penicillin and streptomycin).

Test substances are tested at 11 different concentrations ranging from 10 μΜ to 100 μM. The most potent compounds are tested in the concentration ranges from 1 μΜ to 10 μM or between 100 nM and 1 μM. The medium of the PPARalpha reporter cell line applied on day 1 is completely removed by aspiration, and the test substances diluted in medium are immediately added to the cells. The dilution and addition of substances is performed by a robot (Beckman FX). The final volume of test substances diluted in medium is 100 μl per well of a 96-well microtiter plate. The concentration of DMSO in the assay is less than 0.1% v / v to avoid cytotoxic effects of the solvent.

Each plate was loaded with a standard PPARalpha agonist, which was also diluted at 11 different concentrations, to demonstrate the performance of the assay on each individual plate. The assay plates are incubated in an incubator at 37øC and 5% CO 2 for 24 h.

Day 3

The PPARalpha reporter cells treated with the test substances are removed from the incubator and the medium is aspirated. Cells are lysed by pipetting 50 μl of Bright Glo reagent (from Promega) into each well of a 96-well microtiter plate. After incubation at room temperature in the dark for 10 minutes, the microtiter plates are measured in the luminometer (Trilux de Wallac). The measurement time for each well of a microtiter plate is 1 s.

Evaluation

The luminometer raw data is transferred to a Microsoft Excel file. Dose-effect plots and the 56 EC50 values of PPAR agonists are calculated using the XL.Fit program as specified by the manufacturer (IDBS).

Paralfa EC 50 values for the compounds of Examples 1 to 49 in this assay are in the range of from 5 nM to > 33 μΜ. The compounds of the invention of formula I activate the PPARalpha receptor.

Determination of EC50 values of PPAR agonists in the PPARdelta cellular assay

The potency of substances which bind to human PPARdelta and activate it in an agonist manner is analyzed using a stably transfected HEK (HEK = human embryonic kidney) cell line which is referred to herein as PPARdelta reporter cell line . In analogy to the assay described for PPARalpha, the PPARdelta reporter cell line also contains two genetic elements, a luciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARdelta fusion protein (GR-GAL4-PPARdelta human-LBD) mediating expression of the luciferase reporter element depending on a PPARdelta ligand. Stably expressed and constitutively expressed GR-GAL4-PPAR human-LBD fusion protein binds to the cell nucleus of the PPARdelta reporter cell line through a portion of the GAL4 protein to the GAL4 DNA binding motifs at position 5 'upstream of the luciferase reporter element which is stably integrated into the cell line genome. There is only a small expression of the luciferase reporter gene in the absence of a PPARdelta ligand if fetal calf serum depleted in fatty acids (cs-FCS) is used in the assay. PPARdelta ligands bind and activate the PPARdelta fusion protein and thereby stimulate expression of the luciferase reporter gene. The luciferase that is formed can be detected by chemiluminescence through an appropriate substrate.

Construction of the PPARdelta Reporter Cell Line Production of the stable PPARdelta reporter cell line is based on a stable HEK cell clone that was stably transfected with a luciferase reporter element. This step has already been described above in the " building the PPARalpha reporter cell line " section. In a second step, the PPARdelta fusion protein (GR-GAL4-PPARdelta-LBD human was stably introduced into this cell clone. To this end, the cDNA encoding the N-terminal 76 amino acids of the glucocorticoid receptor Access P04150) was ligated to the cDNA section encoding amino acids 1-147 of the yeast transcription factor GAL4 (Accession No. P04386). The cDNA of the PPARdelta receptor ligand binding domain cDNA (amino acids S139-Y441; N The GR-GAL4-construct prepared in this way (GR-GAL4-PPARdelta-LBD) was recloned on plasmid pcDNA3 (Invitrogen) to allow constitutive expression by cytomegalovirus promoter This plasmid was linearized with a restriction endonuclease and stably transfected into the above-described cell clone containing the luciferase reporter element The PPAR reporter cell line delta derivative containing a luciferase reporter element and constitutively expressed the PPARdelta 58 (GR-GAL4-PPARdelta-LBD) fusion protein was isolated by selection with zeocin (0.5 mg / mL) and G418 (0.5 mg / ml).

Assay Procedure and Evaluation The activity of the PPARdelta agonists is determined in a 3-day test by exact analogy as the procedure already described for the PPARalpha reporter cell line except that the PPARdelta reporter cell line and a specific agonist of PPARdelta as a standard to control the effectiveness of the assay.

EC 50 values of PPARdelta in the range of from 0.2 nM to > 10 μM were measured for the PPAR agonists of Examples 1 to 49 described in this application. The compounds of the invention of formula I activate the PPARdelta receptor.

The examples given in Table I serve to illustrate the invention, but not to limit it.

wherein R8 and R10 = H and Z is a bond.

A dashed line means the point of attachment. 59

Table I 6

Example X w Y R 5 R 6 R 10 R 3 R 7 B R 9 1 0 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 bond (CH 3) 2 3 0 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - H-1 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 bond CH 2) 2 P H 8 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - H 2 bond N -CH 2 CH 3 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - CH3 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH3 -CH2 -CH2 -CH2 -CH 2 CH 3 16 -CH 2 -link H-s NHH p-CF 3 CH -CH 2 CH 3 (continued) Τ 9

Example X w Y R 5 R 6 R 10 R 3 R 7 R 9 R 9 η 0 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - CH 2 CH 3 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - H 2 bond -CH 2 CH 3 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - --CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2- CF 3 CH -CF 2 CH 2 CH 3 (continued)

Example X w Y R 5 R 6 R 10 R 3 R 7 B R 9 32 -O CH 2 - -CH 2 - H-bond NH - H NH - -CH 2 --CH 2 --CH 2 --CH 2 --CH 2 --CH 2 --CH 2 --CH 2 --CH 2 --CH 3 - CH 2 - CH 3 - -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH -CF 3 CH -CH 2 CH 3 40 0 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - H 2 s N -OCH 3 HH p-CF 3 CH -CH 2 CH 3 43 0 -CH 2 -CH 3 -CH 2 CH 3 CH 3 -CH 2 CH 3 CH 3 -CH 2 CH 3 CHF X W Y R 5 R 6 or R 5 R 6 R 7 R 9 R 9 R 9 R 9 R 9 R 9 R 9 45 -CH 2 -CH 2 -CH 2 CH 3 -CH 2 CH 3 -CH 2 CH 3 - bond H-SN -OCH2CF3 HF p-CF3 CH -CH2CH3 48 0 -CH2- bond H-s N -OCH2CF3 HH p-CF3 CH -CH2CH3 The potency of some of the examples described in the GAL4 assays are set forth in the following table: (a)

Example PPARdelta EC50 (μΜ) PPARalpha EC50 (μΜ) 4 0.0002 0.012 10 0.006 4.38 16 0.001 0.117 20 0.001 0.307 22 0.017 2.64 25 0.003 0.544 27 0.017 1.21 32 0.127> 33 34 0.001 1.07 35 0.004 0.296 37 0.0005 0.223 (+) -40 0.001 0.677 42 0.008> 33 (+) -45 0.0003 1.23 48 0.001 0.087

Processes general formula I as outlined in accordance with the invention reaction schemes

Compounds of the formula can be obtained below:

Process A, R5

X = HO. HS, HOCH 3 -, HSCH 2 -, base. (R = halide, SO2R ') or reaction conditions of Mitsunobu (R = OH), Rs, R5

Y

And

R 3, R 2,

1. phenyl chloroformate, pyridine

2. DBU, MeCN or phenyl chloroformate iPrjNEt, MW,

A compound of formula A-2 wherein X 'is -OH, -SH, -CH 2 OH or -CH 2 SH and R 1, R 2, R 3 and B are as defined above is reacted with a compound of formula A1 wherein R is (I, Br, Cl) or a sulfonate (OSO2CH3, OSO2C6H4CH3) and R5, R7, R8, R9, R10, U, V, W, Y and Z are as defined above in the presence of a base such as cesium carbonate or sodium hydride in a solvent such as dimethylformamide or with an alcohol of formula Al wherein R = OH and R 5, R 7, R 8, R 9, R 10, R 10, W, Y, and Z are as defined above under Mitsunobu reaction conditions (e.g., triphenylphosphine, diethyl azodicarboxylate) in a solvent such as dichloromethane to give a compound of formula A-3 wherein X = O, S, -OCH 2 - or -SCH 2 -. The compound of formula A-3 is reacted with hydroxylamine hydrochloride in the presence of a base such as triethylamine in a solvent such as tetrahydrofuran and methanol to provide a compound of formula A-4. This reaction can be facilitated by heating the reaction mixture under microwave irradiation. This compound of formula A-4 is converted into the product of general formula A-5 by reaction with phenyl chloroformate in the presence of a base such as pyridine or diisopropylethylamine followed by heating the reaction mixture with microwave irradiation to allow cyclization or, alternatively, isolating the resulting intermediate and treating it with a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene in a solvent such as acetonitrile.

Examples 1-10 and 35-36 were obtained according to process A.

Other compounds may be obtained according to the invention or by known methods. 66

Process B

A compound of the formula wherein X is O, S, CH2 O or CH2 S and R5, R7, R8, R9, R10, U, V, W, Y and Z are as defined above is reacted with a fluoro-nitrile of wherein R 1, R 2, R 3 and B are as defined above in the presence of a base such as cesium carbonate or sodium hydride in a solvent such as dimethylformamide to give a compound of formula B-3 . As described in process A, compound B-3 is treated with hydroxylamine hydrochloride in the presence of a base such as triethylamine in a solvent such as tetrahydrofuran and methanol to obtain a compound of formula B-4. This reaction can be facilitated by heating the reaction mixture under microwave irradiation. Compound B-4 is converted to the product of general formula B-5 by reaction with phenyl chloroformate in the presence of a base such as pyridine or diisopropylethylamine followed by heating the reaction mixture under microwave irradiation to allow cyclization or, alternatively, The resulting intermediate and its treatment with a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene in a solvent such as acetonitrile.

Examples 11-21 and 37-46 were obtained according to method B.

Other compounds may be obtained according to the invention or by known methods.

Process C

A compound of the general formula C-2 wherein R 5, R 7, R 8, R 9, R 10, R 10, R 10, Y, Z, Y, Z and Z are as defined above is reacted with a benzyl bromide of formula Cl wherein B, R2, R3 and R4 are as defined above in the presence of a base, such as sodium hydride in a solvent, such as dimethylformamide to give a compound of formula C-3. As described in process A, compound C-3 is treated with hydroxylamine hydrochloride in the presence of a base, such as triethylamine in a solvent such as tetrahydrofuran and methanol to obtain a compound of formula C-4. This reaction can be facilitated by heating the reaction mixture under microwave irradiation. Compound C-4 is converted to the product of general formula C-5 by reaction with phenyl chloroformate in the presence of a base such as pyridine or diisopropylethylamine followed by heating the reaction mixture under microwave irradiation to allow cyclization or alternatively isolation of the intermediate resulting in its treatment with a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene in a solvent such as acetonitrile.

Examples 21-33 were obtained according to process C.

Process D:

This process is used to synthesize the structural units D-8, which correspond to the general formula A1 of process A, general formula Bl of process B and general formula C-2 of process C, wherein R = OH, R10 = V is N and U, W, Y, Z, R 5, R 7, R 8 and R 9 are as defined above. 69 R8

A 3-oxo carboxylic acid methyl or ethyl ester of formula D-1 wherein R 5, Y and W are as defined above is reacted with sulfuryl chloride or chlorine to produce the corresponding chloride of formula D-2. This compound of formula D-2 is reacted with a benzamide or thiobenzamide of formula D-3, wherein U is S or O and R 7, R 8 and Z are as defined above to give a thiazole or oxazole ester of formula general D-4. The ester of formula D-4 is reduced with a reducing agent, for example lithium aluminum hydride, to the alcohol of formula D-5, wherein R 5, R 7, R 8, U, W, Y and Z are as defined above.

A compound of formula D-5 is treated with an oxidizing agent such as manganese dioxide in a solvent such as dichloromethane to give an aldehyde of formula D-6 wherein W, Y, U, Z, A, R 5, R 7 and R8 are as defined above. The aldehyde of formula D-6 is reacted with a Grignard reagent of formula D-7, wherein R 9 is as defined above to give a secondary alcohol of formula D-8.

Other compounds may be obtained according to the invention or by known methods.

Process E:

This process is used to synthesize the structural units E-3, which correspond to the general formula Al of process A, general formula Bl of process B and general formula C-2 of process C, wherein R = OH, R 9 is -CF 2 R "; R 1 = R 2, R 2 is N and U, W, Y, Z, R 5, R 7 and R 8 are as defined above.

A compound of general formula D-6 (obtained from process D) is treated with a difluorotrimethylsilyl reagent of formula E-1 wherein R " is (C 1 -C 5) alkyl, (C 2 -C 5) alkenyl, (C 0 -C 5) alkylene (C 6 -C 14) aryl, (C 5 -C 5) alkylene- (C 5 -C 15) heteroaryl, (C 3 -C 8) cycloalkyl, (C 3 -C 8) alkylene-C 3 -C 8 cycloalkenyl, wherein alkyl and alkylene are unsubstituted or mono-, di- or trisubstituted with F and aryl, heteroaryl, cycloalkyl and heterocycloalkyl are substituted or mono-, di- or trisubstituted by halogen, (C 1 -C 4) alkyl, -CF 3, -CHF 2 or O (C 1 -C 4) alkyl; in a polar solvent such as tetrahydrofuran with catalytic amounts of a source of fluoride ion, such as KF or tetrabutylammonium fluoride or alternatively with a bromodifluoromethyl reagent of formula E-2 in the presence of indium in a polar solvent such as tetrahydrofuran in a bath to obtain a secondary alcohol of general formula E-3.

Other compounds may be obtained according to the invention or by known methods.

Process F:

This process is used to synthesize the structural units F-3, which corresponds to the general formula C-1 of process C.

A 1-bromo-4-methyl-benzene of Formula F1, wherein B, R1, R2, R3 and R4 are as defined above is reacted with copper cyanide in a polar solvent such as dimethylformamide at elevated temperature such as 150 - 200 ° C to obtain the 4-methyl-benzonitrile of formula F-2. The 4-methyl-benzonitrile of Formula F-2 is brominated by treatment with 72 N-bromosuccinimide in refluxing tetrachloromethane in the presence of a radical initiator such as AIBN to obtain 4-Bromomethyl-benzonitrile of formula F-3.

Process G:

This process is used to synthesize the structural units G-3, which corresponds to the general formula B-2 of process B, wherein B = C (R 4), R 1 = -CH 2 -Nuc and R 2, R 3 and R 4 are as defined .

The fluoro-2-methylbenzonitrile of formula G-1 is brominated by treatment with N-bromosuccinimide in refluxing tetrachloromethane in the presence of a radical initiator such as AIBN to obtain 2-Bromomethyl-benzonitrile of formula G-2. The compound of formula G-2 is reacted with a nucleophile, for example a primary or secondary amine or a sodium salt of a thiol or an alcohol, in a polar solvent, such as dimethylformamide to obtain the compound of formula G- 3. 73

Process Η:

This process is used to synthesize the structural units H-3, which correspond to the general formula B-2 of process B, wherein B = C (R 4), R 1, R 2, R 3 and R 4 are as defined.

A 4-fluoro-2-bromobenzonitrile of formula H-1 is converted into a compound of the general formula H-3 by reacting with a boronic acid or a boronic ester of formula H-2, M 2 may independently be hydrogen or (C 1 -C 8) alkyl. In the case of alkyl, M 1 / M 2 may form a ring system and R 1 is as defined above using a catalytic amount of a transition metal such as palladium and a ligand such as triphenylphosphine in the presence of a base such as, for example, CS 2 CO 3 in a solvent such as DMF / water.

Process I:

This process is used to synthesize the structural units 1-5, which correspond to the general formula B-2 of process B, wherein B = C (R 4), R 1 is -CH 2 CH 2 R and R 2, R 3 and R 4 are as defined. 74 PPh 3 = CHR 1-2 or

• 1 base I-3

CuCN

I-4 H2 / Pd

A 2-bromo-5-fluorobenzaldehyde of the general formula wherein R 2, R 3 and R 4 are as defined above is reacted under Wittig-like reaction conditions with a triphenylphosphoranylidene of formula 1-2 wherein R is (C1- C7) alkyl, wherein alkyl is substituted 1 to 5 times with F; or with a phosphonate of formula 1-2 'wherein R is (C 1 -C 7) alkyl, wherein alkyl is substituted 1 to 5 times with F in the presence of a base such as sodium hydride or with a phosphonium salt of formula general 1-2 " wherein R 1 is C 1 -C 7 alkyl, wherein alkyl is substituted 1 to 5 times with F in the presence of a base such as n-butyllithium in a polar solvent such as tetrahydrofuran to obtain a compound of formula 1-3 wherein R 2, R 3, R 4 and R 5 are as defined above. The bromide of formula 1-3 wherein R 2, R 3, R 4 and R 5 are as defined above is reacted with copper cyanide in a polar solvent such as dimethylformamide at elevated temperature as for example 150-200 ° C to obtain 4-fluoro -benzonitrile of formula 75

wherein R 2, R 3, R 4 and R 5 are as defined above. The double bond of the compound of formula 1-4 may be hydrogenated with hydrogen and a palladium catalyst in a polar solvent such as methanol to obtain the compound of formula 1-5 wherein R2, R3, R4 and R4 are as defined above.

Process J

A compound of formula C-1 wherein R1 = R2 and R3, R5, R7, R8, R9, R10, U, V, W, Y and Z are as defined above is reacted with a nucleophile, e.g. g. sodium methylate, to obtain a compound of formula C-2. A compound of formula C-2 is reacted with hydroxylamine hydrochloride in the presence of a base such as triethylamine in a solvent such as tetrahydrofuran and methanol to obtain a compound of formula C-3. This reaction can be facilitated by heating the reaction mixture under microwave irradiation. A compound of general formula C-3 is converted to the product of general formula C-4 by reaction with phenyl chloroformate in the presence of a base such as pyridine or diisopropylethylamine followed by heating the reaction mixture with microwave irradiation to allow cyclization or alternatively , isolating the resulting intermediate and treating it with a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene in a solvent such as acetonitrile.

Examples 47-49 were obtained according to process J. 77

Process J

A compound of formula I wherein R 5, R 7, R 8, R 9, U, V, W, Y and Z are as defined above is treated with an oxidizing agent such as manganese dioxide in a supporting solvent such as dichloromethane to obtain a ketone of formula wherein R5, R7, R8, R9, U, V, W, Y and Z are as defined above. A 4-bromomethyl benzonitrile of formula K-3, wherein R1, R2, R3, R4 and B are as defined above is reacted with a phosphite such as triethyl phosphite under elevated temperature such as 120-180 ° C to obtain a phosphonate of formula K-4 wherein R 1, R 2, R 3, R 4 and B are as defined above. The phosphonate of formula K-4 wherein R 1, R 2, R 3, R 4 and B are as defined above and the ketone of formula K-2 wherein R 5, R 7, R 8, R 9, U, V, W, Y and Z are as defined above are made

reacting under Wittig conditions in the presence of a base such as sodium hydride in a polar solvent such as tetrahydrofuran to obtain the compound of formula K-5 wherein R 1, R 2, R 3, R 4, R 5, R 7, R 8, R 9, B , U, V, W, Y and Z are as defined above. The double bond of the compound of formula K-5 is hydrogenated with hydrogen and a palladium catalyst in a polar solvent such as methanol to give the compound of formula K-6 wherein R1, R2, R3, R4, R5, R7, R8 R9, B, U, V, W, Y and Z are as defined above. As described in process A, the compound K-6 wherein R 1, R 2, R 3, R 4, R 5, R 7, R 8, R 9, B, U, V, W, Y and Z are as defined above is treated with hydroxylamine hydrochloride in the presence of a base such as triethylamine in a solvent such as tetrahydrofuran and methanol to obtain a compound of formula K-7 wherein R 1, R 2, R 3, R 4, R 5, R 7, R 8, R 9, B, U, V , W, Y and Z are as defined above. This reaction can be facilitated by heating the reaction mixture under microwave irradiation. Compound K-7 is converted to the product of general formula K-8 wherein R 1, R 2, R 3, R 4, R 5, R 7, R 8, R 9, B, U, V, W, Y and Z are as defined above by reaction with phenyl chloroformate in the presence of a base such as pyridine or diisopropylethylamine followed by heating the reaction mixture under microwave irradiation to allow cyclization or alternatively isolation of the resulting intermediate and treatment thereof with a base such as 1,7-diazabicyclo [5.4 .0] undec-7-ene in a solvent such as acetonitrile. Example 34 was obtained according to method K.

Process L:

This process is used to synthesize the structural units L-3, which corresponds to the general formula B-2 of process B, wherein B = C (R 4), R 1 = OR, R is (C 1 -C 4) alkyl or alkylene ( C0-C2) -cycloalkyl wherein alkyl and alkylene are unsubstituted or mono, di- or trisubstituted with F, and wherein R2, R3 and R4 are as defined above.

The arylethyl ether of formula L-1 wherein R 2, R 3 and R 4 are as defined above, is demethylated by treatment with aluminum trichloride in dichloroethane at reflux to give the phenol of formula L-2. The phenol of formula L-2 is reacted with an electrophile RX, wherein X is an leaving group, such as halide or a sulfonate in a polar solvent such as dimethylformamide in the presence of a base such as potassium carbonate to obtain a compound of general formula L-3. When methyl chlorodifluoroacetate is used as the electrophile and the reaction mixture is heated to 60-120 ° C in a solvent, such as dimethylformamide or dimethylacetamide, the compound of formula L-3 wherein R is CHF2 is obtained.

Other compounds may be obtained according to the invention or by known methods.

Process M:

This process is used to synthesize the structural units M-2, which corresponds to the general formula B-2 of process B, wherein B = C (R 4), R 1 = OR, R is (C 1 -C 4) alkyl or alkylene ( C0-C2) -cycloalkyl wherein alkyl and alkylene are unsubstituted or mono, di- or trisubstituted with F, and wherein R2, R3 and R4 are H.

M-2 M-1 2,4-difluoro-benzonitrile of formula M-1 is treated with an alcohol ROH in a solvent, such as tetrahydrofuran in the presence of a base, such as 0-5 potassium tert-butoxide To give the ether of formula M-2 wherein R is (C 1 -C 4) alkyl or (C 0 -C 2) alkylene-C 3 -C 6 cycloalkyl wherein alkyl and alkylene are unsubstituted or mono-, di- or trisubstituted with F.

Other compounds may be obtained according to the invention or by known methods. 81

Process N:

This process is used to synthesize the structural units N-4 and N-7, which correspond to the general formula A1 of process A wherein R = OH, general formula B-1 of process B wherein X is O, and general formula C-2 of process C, wherein W is CH2, R10 is Η, Z is bond, and U, V, Y, R5, R7 and R8 are as defined above, and R9 is H for N-4 or as defined above for N-7.

Y-R5

The oxazole or thiazole ester of formula N1 wherein R 'is lower alkyl, U, V, R7 and R8 are as defined above, is brominated by treatment with N-bromosuccinimide in tetrachloromethane or dichloromethane at reflux in the presence of a radicals such as AIBN or benzoyl peroxide to produce the brominated product of formula N-2. The alkyl bromide of formula N-2 is reacted with a nucleophile 82 Y-R5, wherein Y is OH or Y is NH (R6) and R5, R6 are as defined above, in a polar solvent such as acetonitrile in the presence of a base such as potassium carbonate to obtain a compound of formula N-3. The ester of formula N-3 is reduced with a reducing agent, such as lithium aluminum hydride, to the alcohol of formula N-4. A compound of formula N-4 is treated with an oxidizing agent such as manganese dioxide in a solvent such as dichloromethane to give an aldehyde of formula N-5, wherein Y, U, V, R 5, R 7 and R 8 are as defined above. The aldehyde of formula N-5 is reacted with a Grignard reagent of formula N-6, wherein R 9 is as defined above to give a secondary alcohol of the formula N-7.

Other compounds may be obtained according to the invention or by known methods.

List of abbreviations:

Ac acetyl AIBN 2,2'-azobis (2-methylpropionitrile)

Bn benzyl iBu isobutyl tBu tert-Butyl

BuLi n-butyl lithium 83 Βζ benzoyl chloride (I) Cyclohexyl DBU 1,8-diazabicyclo [5.4.0] undec-7-ene DEAD diethyl azodicarboxylate DCI Direct chemical ionisation (MS) DCM dichloromethane DMAP N , N-dimethylaminopyridine DMF N, N-dimethylformamide DMSO dimethylsulfoxide EE ethyl acetate and equivalents EI Electronic Impact Ionization (ESI) ESI Electrospray Ionization FG Functional group F-TEDA 1-chloromethyl-4- fluoro-1,4-diazoniabicyclo [2.2.2] octane 84

Hal halogen HPLC High performance liquid chromatography LC-MS liquid chromatography coupled with LG mass spectroscopy Meter MCPBA Meta-chloroperbenzoic acid MS mass spectroscopy MsCl Methanesulfonyl chloride MW microwave NBS N-bromosuccinimide NMR Nuclear magnetic resonance P for Pd P-toluenesulfonic acid Rf retention factor (TLC) SFC Supercritical fluid chromatography TBAF Tetrabutylammonium fluoride Tertiary TLC Thin layer chromatography TMS trimethylsilyl Other compounds of the formula I can be prepared accordingly or by known processes.

The experimental procedures for preparing the above-mentioned examples are described below: Synthesis of Structural Unit according to process D: 86 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol

4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde

18.5 g of [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -methanol11 was dissolved in 200 ml of dichloromethane. 65.3 g of manganese (IV) oxide (activated with charcoal) was added and the resulting mixture was heated under reflux for four hours. The cooled reaction mixture was filtered through a pad of celite. The filtrate was evaporated in vacuo to give 17.1 g of 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde as a pale yellow solid. 1 document 1586573 87 C 12 H 8 F 3 NOS (271.26), MS (ESI): 272.1 (M + H +). 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol

F F

O F

MeMgBr, THF, -78 ° C F F

F

2.5 g of 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde were dissolved in 100 ml of tetrahydrofuran. At 0 ° C, 3.38 ml of a one molar solution of methylmagnesium bromide in tetrahydrofuran were added dropwise. The cooling bath was removed and the reaction stirred at room temperature for one hour. The reaction mixture was then poured into 100 mL of ice-cold saturated NH 4 Cl solution and extracted five times with 80 mL portions of ethyl acetate. The combined organic layers were washed with 100 mL of saturated aqueous sodium chloride solution, then dried over MgSO4. The solvent was evaporated to give 2.7 g of crude 1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol as a pale yellow solid which was used without further purification. C13 H12 F3 NOS (287, 36), MS (ESI): 288.1 (M + H +). 2-Methyl-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] propan-1-ol

According to the method described for 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol, 2-Methyl-1- [4-methyl-2- trifluoro-methyl-phenyl) -thiazol-5-yl] -propan-1-ol from 4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde and isopropylmagnesium bromide. C15 H16 F3 NOS (315.36), MS (ESI): 316.1 (M + H +). 3-methyl-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -butan-1-ol

According to the method described for 3-methyl-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -trifluoromethyl-phenyl) -thiazol-5-yl] -butan-1-ol from 4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde and isobutylmagnesium bromide. C 16 H 18 F 3 NOS (329.39), MS (ESI): 330.0 (M + H +). 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol

According to the method described for 1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol, 1- [4-methyl-2- (4-trifluoromethyl-phenyl ) -thiazol-5-yl] -propan-1-ol from 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde and ethylmagnesium bromide. C14 H14 F3 NOS (301.33), MS (ESI): 302.0 (M + H +).

To a solution of racemic 1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol (10.48 g) in tetrahydrofuran (210 mL) 9 g of (R) - (-) - α-methoxyphenylacetic acid, 40 mL of a molar solution of N, N-dicyclohexylcarbodiimide in dichloromethane and a few mg of N, N-dimethylaminopyridine. The resulting mixture was stirred at room temperature for 1 hour, then filtered. The filtrate was concentrated under reduced pressure and the diastereomers were separated by silica gel column chromatography (gradient from heptane 100 to heptane / ethyl acetate 10) to give: 4.09 g of (S) -1- [ (+) - (R) -methoxy-phenyl-acetic acid 4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propyl ester (less polar fraction) according to the NMR analysis of ¹²C 23 H 22 F 3 NO 3 S And (R) -1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazole-5-carboxylic acid ester, 5.42 g (449.50 g, MS (ESI): 450.1 (M + H + (R) -methoxy-phenyl-acetic acid (more polar fraction) according to 1 H NMR analysis C 23 H 22 F 3 NO 3 S (449.50), MS (ESI): 450.1 (M + H +). 2 Trost, B.M.; Belletire, J.L.; Godleski, S.; McDougal, P.G .; Balkovec, J.M.J. Org. Chem. 1986, 51, 2370 (+) - (R) -1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol

To a solution of 3.74 g of (-) - (R) -methoxy-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] in 19 mL of tetrahydrofuran and 19 mL of ethanol at 0 ° C was added dropwise 24.5 mL of a 91 1

Trost, B.M .; Belletire, J.L .; Godleski, S .; McDougal, P.G .; Balkovec, J.M.J. Org. Chem. 1986, 51, 2370 molar sodium hydroxide in 20.4 mL of water. The resulting mixture was stirred at 0øC for 15 minutes, then 24.5 mL of a 5N hydrochloric acid solution in 20 mL of water was added. After removal of the organic solvents under vacuum, the mixture was extracted with ethyl acetate, filtered through a paper-towel filter with silica and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane 90 / ethyl acetate 10) to give 2.09 g of (+) - (R) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) ) -thiazol-5-yl] -propan-1-ol. C14 H14 F3 NOS (301.33), MS (EI): 301 (M +). (-) - (S) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol

Oh f

According to the method described for (+) - (R) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol, - (S) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol by saponification of (S) -1- [4-methyl-2 - (R) -Methoxy-phenyl-acetic acid (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propyl ester. C14 H14 F3 NOS (301.33), MS (ESI): 302.2 (M + H +). 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -pentan-1-ol

F

According to the method described for 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol, 1- [4-

2-yl) -pentan-1-ol from 4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde and Butylmagnesium bromide . C16 H18 F3 NOS (329.39), MS (ESI): 330.1 (M + H +), Rf (n-heptane: ethyl acetate = 1: 1) = 0.46. 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -2-phenyl-ethanol

According to the method described for 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol, 1- [4-Methyl-2- (4-trifluoromethyl-phenyl ) -thiazol-5-yl] -2-phenyl-ethanol from 4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde and benzylmagnesium bromide. 93 C 19 H 16 F 3 NOS (363.40), MS (ESI): 364.0 (M + H +). 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -2-pyridin-2-yl-ethanol

1.4 ml of a solution of 3M ethylmagnesium bromide solution was added to a solution of 0.44 ml of 2-picoline in 40 ml of dibutyl ether. The reaction mixture was stirred at 140 ° C for forty minutes. Thereafter, a stream of argon was bubbled through the reaction mixture for ten minutes. The mixture was cooled to 70 ° C, 1.0 g of 4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde dissolved in 50 mL of tetrahydrofuran was added, and stirred at ambient temperature for thirty minutes. The reaction mixture was poured onto ice and extracted three times with 80 mL portions of ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo to give 1.49 g of crude 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -2-pyridin-2-yl-ethanol as a oil. This material was used without purification. C18H15F3N20S (364.39), MS (ESI): 365.1 (M + H +),

Rf (n-heptane: ethyl acetate = 1.1) = 0.08. 94 2- (4-Fluoro-phenyl) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol

According to the method described for 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol, 2- (4-Fluoro-phenyl) -1- [4- methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-11] -ethanol from 4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde and 4-fluorobenzylmagnesium bromide. C13 H13 F3 N2 O (302.32), MS (ESI): 303.1 (M + H +).

[4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -phenyl-methanol

According to the method described for 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol, [4-Methyl-2- (4-trifluoromethyl-phenyl) thiazol-5-yl] -phenyl-methanol from 4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde and phenylmagnesium chloride. 95 C 19 H 15 F 4 NOS (381.40), MS (ESI): 382.0 (M + H +). 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -3-phenyl-prop-2-yn-1-ol

According to the method described for 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol, 1- [4-Methyl-2- (4-trifluoromethyl-phenyl ) -thiazol-5-yl] -3-phenyl-prop-2-yn-1-ol from 4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde and phenylethynylmagnesium bromide. C 20 H 14 F 3 NOS (373.40), MS (ESI): 374.0 (M + H +). 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -3-phenyl-propan-1-ol

1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -3-phenyl-propan-1-ol was obtained by hydrogenation of 1- [4- trifluoromethyl-phenyl) -thiazol-5-yl] -3-phenyl-prop-2-yn-1-ol in methanol was treated with palladium on charcoal (10%) in an atmosphere of hydrogen overnight. C 20 H 18 F 3 NOS (377.43), MS (ESI): 376.1 (M + H +). 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-5-yl] -3-phenyl-prop-2-yn-1-ol

According to the method described for 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol, 1- [4-

2-yl] -3-phenyl-prop-2-yn-1-ol from 4-Methyl-2- (4-trifluoromethyl-phenyl) -oxazole (4-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-5-yl] -methanol1 and manganese (IV) dioxide according to the synthesis described for 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde) and phenylethynylmagnesium bromide. 3 Bioorganic & Medicinal Chemical Letters (2003), 13 (9), 1517-1521. C 20 H 14 F 3 NO 2 (357.34), MS (ESI): 358.1 (M + H +). 97 1

Bioorganic & Medicinal Chemical Letters (2003), 13 (9), 1517-1521. 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-5-yl] -3-phenylpropan-1-ol

1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-5-yl] -3-phenyl-propan-1-ol was obtained by hydrogenation of 1- [ trifluoromethyl-phenyl) -oxazol-5-yl] -3-phenyl-prop-2-yn-1-ol in methanol was treated with palladium on charcoal (10%) in an atmosphere of hydrogen overnight. C 20 H 18 F 3 N 2 O (361.37), MS (ESI): 362.0 (M + H +). Synthesis of the structural unit according to process E: 2,2,2-Trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol

To an ice cold solution of 1.0 g of 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde and 0.55 ml of (trifluoromethyl) trimethylsilane in 10 ml of tetrahydrofuran was added 100 mg of tetrabutylammonium fluoride. The reaction mixture was stirred at room temperature for thirty minutes. Thereafter, 20 mL of 2N HCL was added and the mixture stirred at room temperature for thirty minutes. The mixture was extracted three times with 50 mL portions of ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo to give 2,2,2-Trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol as a solid. C13 H9 F6 NOS (341.28), MS (ESI): 342.0 (M + H +), Rf (n-heptane: ethyl acetate = 1: 1) = 0.54. 2,2-Difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -but-3-en-1-ol

To a solution of 1.0 g of 4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde and 868 mg of 3-bromo-3,3-difluoropropene in 10 ml of dimethylformamide were added 425 mg of indium and the resulting suspension was stirred in an ultrasonic bath for two hours. Thereafter, 20 ml of 1N hydrochloric acid was added and the mixture was stirred at room temperature for thirty minutes. The mixture was extracted three times with 50 mL portions of ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was purified by reverse phase HPLC to give 740 mg of 2,2-Difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -but-3- en-1-ol as a colorless lyophilisate. C15H12F5NOS (349.32), MS (ESI): 350.1 (M + H +), Rf (n-heptane: ethyl acetate = 1: 1) = 0.52. 2,2-Difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-11] -butan-1-ol

F

740 mg of 2,2-Difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -but-3-en-1-ol in 50 ml of ethyl. 50 mg of palladium (5% on carbon) was added and the reaction stirred at room temperature under an atmosphere of hydrogen. After 3 hours the catalyst was filtered and the filtrate evaporated in vacuo to give 720 mg of 2,2-difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -butan- 1-ol as a white solid. C15 H14 F5 NOS (351.34), MS (ESI): 352.1 (M + H +). 100 2-Cyclopropyl-2,2-difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol

To an ice cold solution of 365 mg of 2,2-difluoro-1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -but-3-en-1-ol in 10 ml of pyridine 5 mL of acetic acid anhydride was added. The ice bath was removed and the reaction stirred at room temperature for one hour. Ice was added and the reaction mixture diluted by the addition of 100 mL of dichloromethane. The organic layer was separated and washed with 50 mL of water, 1 M HCl, saturated NaHCO 3 solution and saturated aqueous sodium chloride solution. Then, the organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting residue was dissolved in 30 mL of diethyl ether (flask 1). 246 mg of palladium (II) acetate was added and the mixture cooled in an ice bath. In a second flask 4.0 g of N-methyl-N-nitroso-p-toluenesulfonamide were suspended in 30 ml of ethanol. A stream of argon was continuously bubbled through the flask2 and then through flask 1. 2N NaOH was added dropwise to flask 2 until the dissolution of N-methyl-N-nitroso-p-toluenesulfonamide, then the stream of argon. The reaction mixture (flask 1) was stirred at 0øC for an additional hour. Then, 10 mL of acetic acid was added and the reaction mixture diluted by addition of 80 mL of ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The solvent was removed in vacuo. The resulting residue was dissolved in 20 mL of methanol, 1 mL of sodium methylate solution (30%) was added and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was then neutralized by the addition of acetic acid, the solvent was removed in vacuo and the residue purified by reverse phase HPLC to obtain 120 mg of 2-Cyclopropyl-2,2-difluoro-1- [4-methyl-2 - (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethane as lyophilized. C16 H14 F5 NOS (363.35), MS (ESI): 364.1 (M + H +). 2- (4-Difluoromethyl-phenyl) -2,2-difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol

A solution of 1.0 g of 4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carbaldehyde and 1.42 g of 4- (bromodifluoromethyl) -1- (difluoromethyl) benzene in 10 ml of dimethylformamide was added 508 mg of indium and the resulting suspension was stirred in an ultrasonic bath for twelve hours. Then, an additional 1.42 g of 4- (bromodifluoromethyl) -1- (difluoromethyl) benzene and 508 mg of indium was added and the resulting suspension was stirred in an ultrasonic bath for a further twelve hours. Thereafter, 20 ml of 1 N hydrochloric acid was added and the mixture stirred at room temperature for thirty minutes. The mixture was extracted three times with 50 mL portions of ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was purified by reverse phase HPLC to obtain 620 mg of 2- (4-Difluoromethyl-phenyl) -2,2-difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) 5-yl] -ethanol as a colorless lyophilisate. C 20 H 14 F 7 NOS (449.39), MS (ESI): 450.1 (M + H +). Synthesis of the structural unit according to the procedure N: 1- [2- (4-Trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propan-1-ol

103 4-Bromomethyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid ethyl ester1

To a solution of 200 g of commercially available 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid ethyl ester in 1.6 L of dichloromethane was added 20.5 g of benzoyl peroxide and 124 g of NBS. The resulting mixture was refluxed in the dark for 22 h. After cooling to 0øC, the mixture was filtered. The filtrate was concentrated to half volume under reduced pressure, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a white solid. The solid was recrystallized from 900 mL of diisopropyl ether 80 / dichloromethane 20 to give a first crop of 101 g of 4-bromomethyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid ethyl ester. The filtrate was concentrated under reduced pressure, then recrystallized from 300 mL of diisopropyl ether 90 / dichloromethane 10 to give a second culture of 72 g. A total of 173 g of 4-bromomethyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid ethyl ester was obtained as a white solid.

Cl4 H11 BrF3 NO2 S (394, 21), MS (EI): 394 (M +). 2- (4-Trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazole-5-carboxylic acid ethyl ester

To a solution of 107.7 g of 4-trifluoromethylpiperidine hydrochloride in 450 ml of water was added 2.7 L of acetonitrile, 224 g of 4-bromomethyl-2- (4-trifluoromethyl-phenyl) -thiazole acid ethyl ester -5-carboxylic acid and 157 g of potassium carbonate. The resulting mixture was heated at 40 ° C for 2 h, allowed to cool to room temperature, then concentrated under reduced pressure. The residue was taken up in 2 L of dichloromethane, then washed twice with 500 ml of water. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / ethanol gradient from 100/0 to 90/10) followed by washing the collected solid with diisopropyl ether to give 212 g of 2- (4 trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazole-5-carboxylic acid as a white solid. C 20 H 20 F 6 N 2 O 2 S (466.45), MS (EI): 466 (M +). 105 [2- (4-Trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -methanol

To a solution of 220 g of 2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazole-5-carboxylic acid ethyl ester in 2.2 L of tetrahydrofuran At 0 ° C, 250 mL of a 2M solution of lithium aluminum hydride in tetrahydrofuran was added dropwise. The resulting mixture was stirred for 1 h, allowed to warm to room temperature, then slowly poured into 1 L of cold water and extracted twice with 1.5 L of ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was washed with 500 mL of hot diisopropyl ether, then purified by silica gel column chromatography (dichloromethane / ethanol gradient from 100/0 to 90/10) to give 163 g of [2- (4- trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -methanol as a white solid. C18H18F6N20S (424, 41), MS (ESI): 425 (M + H +). 106 2- (4-Trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazole-5-carbaldehyde

To a solution of 1 g of [[2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -methanol in 7 mL of dichloromethane was added 2- 35 g of manganese (IV) oxide (activated with charcoal). The resulting mixture was heated under reflux for four hours. The cooled reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (heptane 80 / ethyl acetate 20) to give 0.53 g of 2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidine ylmethyl) -thiazole-5-carbaldehyde. C18H16F6N20S (422.39), MS (ESI): 423.0 (M + H +). 1- [2- (4-Trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propan-1-ol

To a solution of 530 mg of 2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazole-5-carbaldehyde in 43 ml of tetrahydrofuran at 0 ° C was slowly added 2.2 mL of a molar solution of ethylmagnesium bromide in tert-butyl methyl ether. The reaction mixture was stirred at 0 ° C for one hour, then poured into aqueous KH2 PO4 solution and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide 545 mg of 1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazole -5-yl] -propan-1-ol which was used without further purification. C 20 H 22 F 6 N 2 OS (452, 47), MS (ESI): 453 (M + H +). 108

To a solution of racemic 1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propan-1-ol (R) - (-) - α-methoxyphenylacetic acid, 9 ml of a molar solution of N, N-dicyclohexylcarbodiimide in dichloromethane and a few mg of N, N- dimethylaminopyridine. The resulting mixture was stirred at room temperature overnight, then filtered. The filtrate was concentrated under reduced pressure and the diastereomers were separated by silica gel column chromatography (dichloromethane gradient 100 to dichloromethane 90 / ethyl acetate 10) to give: 1.06 g of (S) -1- [2 (-) - (R) -Methoxy-phenyl-acetic acid (less polar fraction) ) according to 1 H NMR analysis C 29 H 30 F 6 N 2 O 3 S (600.62), MS (ESI): 601.2 (M + H +), and 0.67 g of (R) -1- [2- 4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propyl ester (more polar fraction) from (+) -

according to the H NMR analysis C 29 H 30 F 6 N 2 O 3 S (600.62), MS (ESI): 601.2 (M + H +). (R) -1- [2- (4-Trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propan-1-ol

To a solution of 0.67 g of (R) -1- [2- (4-trifluoromethylphenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] R) -methoxy-phenyl-acetic acid in 2.5 ml of tetrahydrofuran and 2.5 ml of ethanol at 0 ° C was added dropwise 3.5 ml of a molar solution of sodium hydroxide in 2, 7 mL of water. The resulting mixture was stirred at 0 ° C for 15 minutes, then 0.6 mL of a 5N solution of hydrochloric acid in 2.7 mL of water was added. After removal of the organic solvents in vacuo, the

extracted with dichloromethane, filtered through a silica-treated filter and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane 90 / ethyl acetate 10) to give 270 mg of (R) -1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl- piperidin-1-ylmethyl) -thiazol-5-yl] -propan-1-ol. C 20 H 22 F 6 N 2 OS (452, 46), MS (ESI): 453.2 (M + H +). (S) -1- [2- (4-Trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propan-1-ol

According to the method described for (R) -1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propan-1-ol , (S) -1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propan-1-ol was obtained by saponification of ester (S) -1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propyl ester of (R) -methoxy-phenyl-acetic acid . C 20 H 22 F 6 N 2 OS (452, 46), MS (ESI): 453.1 (M + H +). Synthesis of the structural unit according to process F: 4-Bromomethyl-2-chloro-benzonitrile

N

N

Br 'W' " 01 CuCN

Cl

NBS, AIBN

Cl

Br '2-Chloro-4-methyl-benzonitrile

Cl

CuCN

25.0 g of 4-bromo-3-chlorotoluene and 21.8 g of copper (I) cyanide were dissolved in 200 ml of dimethylformamide and stirred at 150 ° C for three hours. The cooled reaction mixture was diluted by the addition of 300 mL of ethyl acetate and washed three times with 150 mL portions of saturated NH 4 Cl solution. The precipitates were filtered and the filtrate dried over MgSO4 and then reduced in vacuo to obtain 17.3 g of 2-Chloro-4-methyl-benzonitrile. This material was used without purification in the next step. C8 H6 ClN (151.60). 112 4-Bromomethyl-2-chloro-benzonitrile

17.3 g of 2-Chloro-4-methyl-benzonitrile were dissolved in 50 ml of tetrachloromethane and heated to reflux. A mixture of 24.3 g of N-bromosuccinimide and 7.48 g of 2,2'-azobis (2-methylpropionitrile) was added in five portions over a period of one hour. The reaction mixture was heated under reflux for an additional three hours. The cooled reaction mixture was then filtered through a pad of celite. The filtrate was washed with 100 mL of saturated NaHCO 3 solution, dried over MgSO 4 and the solvent removed in vacuo. The resulting residue was dissolved in 200 mL of tetrahydrofuran and cooled in an ice bath to 0 ° C. 88.0 mL of diethyl phosphite was added, followed by the addition of 117.0 mL of N, N-diisopropylethylamine. The cooling bath was removed and the reaction stirred at room temperature for four hours. The reaction mixture was poured into 400 mL of 50% NaHCO 3 solution and extracted with 400 mL of diethyl ether. The organic layer was separated and washed with 200 mL of 50% NaHCO 3 solution and 200 mL of water and then dried over MgSO 4. The solvent was removed in vacuo. The resulting residue was purified on silica gel with eluent n-heptane: ethyl acetate = 19: 1 to obtain 13.0 g of 4-bromomethyl-2-chlorobenzonitrile as a solid. 4: 1) C8 H5 BrClN (230.49), Rf (n-heptane: ethyl acetate 0.31, 8-Methyl-guinoline-5-carbonitrile

NCuCN

4.0 g of 8-bromo-5-methyl-quinoline and 1.69 g of copper (I) cyanide were dissolved in 16 ml of dimethylformamide and stirred at 200 ° C for thirty minutes under microwave irradiation. The cooled reaction mixture was poured into 50 mL of 2N HCL and extracted with 100 mL of ethyl acetate. The organic layer was washed with 50 mL of 2N HCl and 30 mL of saturated aqueous sodium chloride solution and then dried over MgSO4. The solvent was removed in vacuo. The resulting residue was purified on silica gel eluting with n-heptane / ethyl acetate = 2: 1 to obtain 3.0 g of 8-Methyl-quinoline-5-carbonitrile.

Cl, H8 N2 (168.20), Rf (n-heptane: ethyl acetate = 4: 1) = 0.20. 114 8-Bromomethyl-quinoline-5-carbonitrile

N

According to the method described for 4-Bromomethyl-2-chloro-benzonitrile, 8-bromomethyl-quinoline-5-carbonitrile was obtained from 8-Methyl-quinoline-5-carbonitrile.

(247.10), Rf (n-heptane: ethyl acetate = 4: 1) = 0.24. 4-Bromomethyl-naphthalene-1-carbonitrile

N

According to the method described for 4-Bromomethyl-2-chloro-benzonitrile, 4-Bromomethyl-naphthalene-1-carbonitrile was obtained from commercially available 1-cyano-4-methylnaphthalene. 115 4: 1) = 0.38. C 12 H 8 BrN (246.11), Rf (n-heptane: ethyl acetate 2-Bromo-4-bromomethyl-benzonitrile

N

Br

Br

According to benzonitrile, from available. 2-bromo-4-bromomethyl-benzonitrile was reacted with commercially available 2-bromo-4-methyl-benzonitrile in the method described for 4-Bromomethyl-2-chloro-C8H5Br2N (274.94), Rf (n-heptane: acetate ethyl = 4: 1) = 0.30. 6-Bromomethyl-2-chloro-nicotinonitrile

116

According to the method described for 4-Bromomethyl-2-chloro-benzonitrile, 6-Bromomethyl-2-chloro-nicotinonitrile was obtained from commercially available 2-Chloro-6-methyl-nicotinonitrile. C 23 H 4 BrClN 2 (231.48), R f (n-heptane: ethyl acetate = 1: 1) = 0.48. 4-Bromomethyl-2-fluoro-benzonitrile

N

F

Br

According to the method described for 4-Bromomethyl-2-chloro-benzonitrile, 4-bromomethyl-2-fluoro-benzonitrile was obtained from commercially available 2-Fluoro-4-methyl-benzonitrile. C8 H5 BrFN (214.04), Rf (n-heptane: ethyl acetate = 4: 1) = 0.25. Synthesis of the structural unit according to process G: 117 4-Fluoro-2-methoxymethyl-benzonitrile

NBS, AIBN

Naomi

F F F 2-Bromomethyl-4-fluoro-benzonitrile

According to the method described for 4-Bromomethyl-2-chloro-benzonitrile, 2-Bromomethyl-4-fluoro-benzonitrile was obtained from commercially available 4-Fluoro-2-methylbenzonitrile. C8 H5 BrFN (214.04), Rf (n-heptane: ethyl acetate = 4: 1) = 0.25. 4-Fluoro-2-methoxymethyl-benzonitrile

N

N

Naomi

F

F 118

1.0 g of 2-bromomethyl-4-fluoro-benzonitrile was dissolved in a mixture of 10 mL of methanol and 10 mL of tetrahydrofuran. 500 mg of sodium methylate was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was poured into 30 mL of water and extracted five times with a 25 mL portion of ethyl acetate. The combined organic layers were dried over MgSO4, the solvent removed in vacuo and the resulting residue purified on silica gel with the eluent heptane = > n-heptane: ethyl acetate = 9: 1 to obtain 526 mg of 4-Fluoro-2-methoxymethyl-benzonitrile as an oil. C 9 H 8 FNO (165.17), R f (n-heptane: ethyl acetate = 9: 1) = 0.25. 4-Fluoro-2- (2,2,2-trifluoro-ethoxymethyl) -benzonitrile

336 μl of 2,2,2-trifluoroethanol were dissolved in 10 ml of dimethylformamide. 243 mg of sodium hydride was added and the mixture stirred at room temperature for one hour. Then, 1.0 g of 2-Bromomethyl-4-fluoro-benzonitrile was added in one portion and the reaction mixture was stirred at room temperature for three hours. The reaction mixture was poured into 50 mL of water and extracted five times with a 25 mL portion of ethyl acetate. The combined organic layers were dried over MgSO4, the solvent removed in vacuo and the resulting residue purified on silica gel with eluent heptane = > n-heptane: ethyl acetate = 4: 1 to obtain 750 mg of 4-Fluoro-2- (2,2,2-trifluoro-ethoxymethyl) -benzonitrile.

ClOH 7 F 4 NO (233.17), R f (n-heptane: ethyl acetate = 4: 1) = 0.31. 2-Ethoxymethyl-4-fluoro-benzonitrile

N

F

According to the method described for 4-Fluoro-2- (2,2,2-trifluoro-ethoxymethyl) -benzonitrile, 2-Ethoxymethyl-4-fluoro-benzonitrile was obtained from 2-bromomethyl-4-fluoro-benzonitrile and ethanol. C 10 H 10 FNO (179.20). Synthesis of the structural unit according to process H: 2-Cyclopropyl-4-fluoro-benzonitrile

Br r P (Cy) 3. Pd (OAc) 2

F 120

500 mg of commercially available 2-Bromo-4-fluorobenzonitrile, 70 mg of tricyclohexylphosphine, 2.04 g of tripotassium phosphate monohydrate and 278 mg of cyclopropylboronic acid were placed in a reaction vessel and 11 ml of toluene were added. The mixture was degassed with argon, then 561 mg of palladium (II) acetate was added and the reaction stirred at 100 ° C for 1.5 hours. To the cooled reaction mixture was added 30 mL of water and the mixture was extracted five times with 30 mL portions of ethyl acetate. The combined organic layers were dried over MgSO4, the solvent removed in vacuo and the resulting residue purified on silica gel with the eluent heptane = > n-heptane: ethyl acetate = 5: 1 to give 310 mg of 2-Cyclopropyl-4-fluoro-benzonitrile as a yellow solid. C 10 H 8 FN (161.18), R f (n-heptane: ethyl acetate = 4: 1) = 0.48. 5,4'-Difluoro-biphenyl-2-carbonitrile

According to the method described for 2-Cyclopropyl-4-fluoro-benzonitrile, 5,4'-Difluoro-biphenyl-2-carbonitrile was obtained from 2-Bromo-4-fluorobenzonitrile and 4-fluorobenzene boronic acid. C13 H7 F2 N (215.20). Synthesis of the structural unit according to process I: 2-Ethyl-4-fluoro-benzonitrile

1-Bromo-4-fluoro-2-vinyl-benzene

21.12 g of methyltriphenylphosphonium bromide were suspended in 150 ml of tetrahydrofuran and cooled in an ice bath. 21.68 ml of n-butyl lithium (2.5 M in n-heptane) were added dropwise and the reaction mixture stirred at 0 ° C for thirty minutes. Thereafter, 10.0 g of commercially available 2-bromo-5-fluorobenzaldehyde was slowly added so that the reaction temperature did not exceed + 5 ° C. Upon completion of the addition, the cooling bath was removed and the reaction stirred at room temperature for 122 hours. The reaction mixture was diluted by the addition of 300 mL of ethyl acetate and washed three times with 120 mL portions of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, the solvent removed in vacuo and the resulting residue purified on silica gel with eluent heptane = > n-heptane: ethyl acetate = 9: 1 to give 7.9 g of 1-Bromo-4-fluoro-2-vinyl-benzene as an oil. C8 H6 BrF (201.04), Rf (n-heptane: ethyl acetate = 9: 1) = 0.61. 4-Fluoro-2-vinyl-benzonitrile

4.0 g of 1-Bromo-4-fluoro-2-vinyl-benzene and 1.8 g of copper (I) cyanide were dissolved in 16 ml of dimethylformamide and heated under microwave irradiation at 200 ° C for 25 hours. minutes. The cooled reaction mixture was poured into 200 ml of 1 M HCl and extracted five times with 60 ml portions of ethyl acetate. The combined organic layers were washed with 100 mL of 1N HCl, dried over MgSO4, then the solvent was removed in vacuo and the resulting residue purified on silica gel eluting with heptane = n-heptane: ethyl acetate = 6: 1 to obtain 1.77 g of 4-Fluoro-2-vinyl-benzonitrile as a solid. C 9 H 6 FN (147.15), R f (n-heptane: ethyl acetate = 4: 1) = 0.33. 123 2-Ethyl-4-fluoro-benzonitrile

800 mg of 4-Fluoro-2-vinyl-benzonitrile were dissolved in 5 mL of methanol. 80 mg of palladium (10% on charcoal) was added and the reaction was stirred under an atmosphere of hydrogen for one hour. The catalyst was filtered through a pad of celite. The filtrate was evaporated to give 625 mg of 2-Ethyl-4-fluoro-benzonitrile. C 9 H 8 FN (149.17), R f (n-heptane: ethyl acetate = 4: 1) = 0.37. Synthesis of the structural unit according to the procedure L: 2-Difluoromethoxy-4-fluoro-benzonitrile

AlCl 3 DCE reflux

4-Fluoro-2-methoxy-benzonitrile was prepared according to a previous publication: 1 To a solution of 1 g of 4-fluoro-2-methoxybenzonitrile in 15 ml of dichloroethane was added 1.1 g JP9143139 1.1 g of aluminum trichloride. The resulting mixture was refluxed for 1 day, then slowly poured into water and extracted with ethyl acetate. The organic extracts were washed twice with 10% aqueous sodium hydroxide solution. The combined basic layers were washed twice with ethyl acetate, acidified with concentrated aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts were washed with water, saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.78 g of 4-fluoro-2-hydroxy-benzonitrile as a white solid . C7 H4 FNO (137.11), MS (ESI): 138.17 (M + H +). To a solution of 4.6 g of 4-fluoro-2-hydroxy-benzonitrile in 15 ml of anhydrous dimethylacetamide was added 6.8 g of methyl chlorodifluoroacetate and 6.5 g of potassium carbonate. The resulting mixture was degassed by bubbling argon therethrough and heated to 110 ° C for 2 h, then a further 6.5 g of methyl chlorodifluoroacetate and 6.5 g of potassium carbonate were added. The resulting mixture was heated to 110 ° C for an additional hour, then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed twice with aqueous sodium hydroxide solution, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient from heptane 100 to heptane 80 / ethyl acetate 20) to give 4.78 g of 2-difluoromethoxy-4-fluoro-benzonitrile as a yellowish liquid. 125 C8 H4 F3 NO (187.12), MS (ESI): 188.0 (M + H +). 2-Difluoromethoxy-4,5-difluoro-benzonitrile

F F

N F

F To a solution of 1 g of commercially available 4,5-difluoro-2-hydroxy-benzonitrile in 5 ml of anhydrous dimethylacetamide was added 1.3 g of methyl chlorodifluoroacetate and 1.28 g of potassium carbonate. The resulting mixture was degassed by bubbling argon therethrough and heated at 110 ° C for 1.5 h, then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed twice with aqueous sodium hydroxide solution, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient from heptane 100 to heptane 80 / ethyl acetate 20) to give 0.42 g of 2-difluoromethoxy-4,5-difluoro-benzonitrile as a yellowish liquid. C8 H3 F4 NO (205, 11), MS (EI): 205 (M +). Synthesis of the structural unit according to process M: 126 4-Fluoro-2- (2,2,2-trifluoro-ethoxy) -benzonitrile

F

N

CF3CH3OH KOtBu

N F

To a solution of 359 mg of trifluoroethanol in 3 ml of anhydrous tetrahydrofuran at 5øC were slowly added 3.6 ml of a molar solution of potassium tert-butoxide in tert-butanol. The resulting solution was stirred for 30 minutes at 5 ° C and slowly added to a solution of 500 mg of 2,4-difluoro-benzonitrile in 3 ml of anhydrous tetrahydrofuran at 5 ° C. The resulting mixture was stirred for 1 h at 5 ° C, then poured into water and extracted with ethyl acetate. The organic extracts were dried over

magnesium, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient from heptane 100 to heptane 90 / ethyl acetate 10) to give 640 mg of 4-fluoro-2- (2,2,2-trifluoroethoxy) benzonitrile as a white solid. C 9 H 5 F 4 NO (219.14), MS (ESI): 220 (M + H +).

The following examples were prepared according to process A: 127

Example 1 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [1,2,4- ] oxadiazol-5-one

1. phenylene chioroformate, pyridine, DCM

2. DBU, MeCN 2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} -benzonitrile

2.0 g of 1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol and 1.18 g of 2-chloro-4-hydroxybenzonitrile were dissolved in 50 ml of tetra -hydrofuran. At -20 ° C 2.74 g of triphenylphosphine and 1.82 g of diethyl azodicarboxylate were added. The cooling bath was removed and the reaction stirred at room temperature for four hours. The reaction mixture was then poured into 100 mL of ice-cold saturated NH 4 Cl solution and extracted five times with 80 mL portions of ethyl acetate. The combined organic layers were washed with 100 mL of saturated aqueous sodium chloride solution, then dried over MgSO4. The solvent was evaporated in vacuo and the resulting residue purified by silica gel chromatography with eluent n-heptane: ethyl acetate = 4: 1 to obtain 2.1 g of 2-chloro-4- {1- [4-methyl -2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} -benzonitrile as a pale yellow solid. C20 H14 ClF3 N2 OS (422.86), MS (ESI): 422.9 (M + H +). 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [1,2,4] oxadiazole -5-one

2.1 g of 2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} -benzonitrile were dissolved in a mixture of 20 mL of tetrahydrofuran and 20 mL of methanol. 3.29 g of hydroxylamine hydrochloride followed by the addition of 5.74 ml of triethylamine were added. The reaction mixture was stirred at 60 ° C overnight. The solvents were removed in vacuo and the resulting residue poured into water and extracted five times with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO 4, and the solvent was evaporated in vacuo. The residue was dissolved in 10 mL of dichloromethane. 0.50 mL of pyridine and 0.77 mL of phenyl chloroformate was added and the mixture stirred at room temperature for fifteen minutes. The mixture was diluted by the addition of 25 mL of acetonitrile and 3.54 mL of 1,8-diazabicyclo [5.4.0] undec-7-ene were added. The mixture was stirred at room temperature for thirty minutes. The mixture was evaporated in vacuo and the resulting crude material was purified by RP-HPLC to obtain 0.50 g of 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl ) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one. The racemate was separated into its enantiomers by chiral phase chromatography (Chiralpak AD-H / 40) with the eluant n-heptane: propanol = 5 + 1, R t = 5.4 min and 7.4 min. C21 H15 ClF3 N3 O3 S (481.88), MS (ESI): 482.1.

Example 2 3- (2-Chloro-4- {2-methyl-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [1 , 2,4] oxadiazol-5-one

According to the method described for 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, there was obtained 3- (2-chloro-4- {2-methyl-1- [4- [2- (4-trifluoromethyl-phenyl) -thiazol-5- 2-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -amide propan-1-ol and 2-chloro-4-hydroxybenzonitrile. The racemate was separated into its enantiomers by chiral phase chromatography (Chiralpak AD-H / 40) with eluent n-heptane: propanol = 5 + 1, Rt = 6.3 min and 11.3 min. C23 H19 ClF3 N3 O3 S (509.94), MS (ESI): 510.1 (M + H +).

Example 3 3- (2-Chloro-4- {3-methyl-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -butoxy] -phenyl) -4H- [1 , 2,4] oxadiazol-5-one

F

According to the method described for 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [1,2. 4-oxadiazol-5-one, 3- (2-chloro-4- {3-methyl-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -butoxy} 3-yl) -4H- [1,2,4] oxadiazol-5-one was prepared from 3-methyl-1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -butan-1-ol and 2-chloro-4-hydroxybenzonitrile. The racemate was separated into its enantiomers by chiral phase chromatography (Chiralpak AD-H / 40) with eluent n-heptane: propanol = 5 + 2, Rt = 3.5 min and 5.4 min. C24 H21 ClF3 N3 O3 S (523, 97), MS (ESI): 524.2 (M + H +).

Example 4 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [1,2,4- ] oxadiazol-5-one

According to the method described for 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [1,2. 4-oxadiazol-5-one, 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) - 4H- [1,2,4] oxadiazol-5-one from 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol and 2-chloro-4- hydroxybenzonitrile. The racemate was separated into its enantiomers by chiral phase chromatography (Chiralpak AD-H / 40) with eluent n-heptane: propanol = 5 + 2, R t = 6.0 min and 9.7 min. C 22 H 17 ClF 3 N 3 O 3 S (495, 91), MS (ESI): 496.1 (M + H +). 132

Example 5 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -2-phenyl-ethoxy} -phenyl) -4H- [1 , 2,4] oxadiazol-5-one

According to the method described for 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -2- ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one from 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -2- -ethanol and 2-chloro-4-hydroxybenzonitrile. The racemate was separated into its enantiomers by chiral phase chromatography (Chiralpak AD-H / 40) eluting with ethanol: methanol = 1 + 1 + 0.1% trifluoroacetic acid, Rt = 4.5 min and 7.3 min. C27 H19 ClF3 N3 O3 S (557, 98), MS (ESI): 558.1 (M + H +). 133

Example 6 3- (2-Chloro-4 - {[4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -phenylmethoxy} -phenyl) -4H- [1,2,4- ] oxadiazol-5-one

According to the method described for 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-chloro-4 - {[4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -phenylmethoxy} -phenyl ) -4H- [1,2,4] oxadiazol-5-one from [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -phenyl-methanol and 2-chloro-4- hydroxybenzonitrile. The racemate can be separated into its enantiomers by the method described above. C26 H17 ClF3 N3 O3 S (543.96), MS (ESI): 544.1 (M + H +). 134

Example 7 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -3-phenyl-propoxy} -phenyl) -4H- [1 , 2,4] oxadiazol-5-one

According to the method described for 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -3- propoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one was prepared from 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -3- -propan-1-ol and 2-chloro-4-hydroxybenzonitrile. The racemate can be separated into its enantiomers by the method described above. C28 H21 ClF3 N3 O3 S (572.01), MS (ESI): 572.4 (M + H +). 135

Example 8 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-5-yl] -3-phenyl-propoxy} -phenyl) -4H- {1 , 2,4] oxadiazol-5-one

According to the method described for 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-5-yl] -3- propoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one was prepared from 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -oxazol-5-yl] -3-phenyl -propan-1-ol and 2-chloro-4-hydroxybenzonitrile. The racemate can be separated into its enantiomers by the method described above. C28 H21 ClF3 N3 O4 (555.95), MS (ESI): 556.2 (M + H +). 136

Example 9 3- (2-Chloro-4- {2- (4-fluoro-phenyl) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} -phenyl ) -4H- [1,2,4] oxadiazol-5-one

According to the method described for 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-Chloro-4- {2- (4-fluoro-phenyl) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole -5-yl] -ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one from 2- (4-Fluoro-phenyl) -1- [4-methyl- -trifluoromethyl-phenyl) -thiazol-5-yl] -ethane and 2-chloro-4-hydroxybenzonitrile. The racemate was separated into its enantiomers by chiral phase chromatography (Chiralpak AD-H / 39) with the eluant n-heptane: iso-propanol = 2: 1, Rt = 5.75 min and 14.84 min. C27 H18 ClF4 N3 O3 S (575, 97), MS (ESI): 576.2 (M + H +). 137

Example 10 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-11] -2-pyridin-2-yl-ethoxy} -phenyl) - 4H- [1,2,4] oxadiazol-5-one

F

According to the method described for 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -2- 2-yl-ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one from 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -2-pyridin-2-yl-ethanol and 2-chloro-4-hydroxybenzonitrile. The racemate was separated into its enantiomers by chiral phase chromatography (Chiralpak AD-H / 40) with eluent n-heptane: iso-propanol = 2: 1, Rt = 6.87 min and 12.04 min. C26 H18 ClF3 N4 O3 S (558.97), MS (ESI): 559.2 (M + H +), Rf (ethyl acetate) = 0.18.

The following examples were prepared according to process B:

Example 11 3- (2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [ ] oxadiazol-5-one

1. phenyl chloroformate. pyridine. DCM

2. DBU, MeCN 2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -benzonitrile

Br

500 mg of 1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol in 5 ml of dimethylformamide was dissolved. 108 mg of sodium hydride was added and the mixture stirred at room temperature. After thirty minutes commercially available 2-bromo-4-fluorobenzonitrile was added and the reaction mixture stirred at room temperature for 139 hr. Then, 5 mL of water was added and the mixture extracted three times with 30 mL portions of ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed in vacuo. The residue was purified by reverse phase HPLC to obtain 375 mg of 2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -benzonitrile as an oil. C21 H16 BrF3 N2 O (481.34), MS (ESI): 481.0 (M + H +). 3- (2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [1,2,4] oxadiazole -5-one

F

According to the method described for 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl ) -4H- [1,2,4] oxadiazol-5-one was prepared from 2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] - propoxy} -benzonitrile. The racemate can be separated into its enantiomers by the method described above. C 22 H 17 BrF 3 N 3 O 3 S (540.36), MS (ESI): 540.0 (M + H +). 140

Example 12 3- [4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2-trifluoro-ethoxymethyl) -phenyl ] -4H- [1,2,4] oxadiazol-5-one

According to the method described for 3- (2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- [4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,4- 2-trifluoromethoxyphenyl) -4H- [1,2,4] oxadiazol-5-one from 1- [4-Methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propan-1-ol and 4-Fluoro-2- (2,2,2-trifluoro-ethoxymethyl) -benzonitrile. The racemate can be separated into its enantiomers by the method described above. C25H21F6N304S (573.52), MS (ESI): 574.1 (M + H +). 141

Example 13 3- (2-Methoxymethyl-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [1,2,4- ] oxadiazol-5-one

According to the method described for 3- (2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-Methoxymethyl-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl ) -4H- [1,2,4] oxadiazol-5-one was prepared from 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol and 4 -Fluoro-2-methoxymethyl-benzonitrile. The racemate can be separated into its enantiomers by the method described above. C24H22F3N304S (505.52), MS (ESI): 506.1 (M + H +). 142

Example 14 3- (2-Ethoxymethyl-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [1,2,4- ] oxadiazol-5-one

F

According to the method described for 3- (2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-Ethoxymethyl-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl ) -4H- [1,2,4] oxadiazol-5-one from 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol and 2- -Etoxymethyl-4-fluoro-benzonitrile. The racemate can be separated into its enantiomers by the method described above. C25 H24 F3 N3 O4 S (519.55), MS (ESI): 520.1 (M + H +). 143

Example 15 3- (2-Ethyl-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-11] -propoxy} -phenyl) -4H- [1,2,4- ] oxadiazol-5-one

According to the method described for 3- (2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-Ethyl-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl ) -4H- [1,2,4] oxadiazol-5-one from 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol and 2- -Ethyl-4-fluoro-benzonitrile. The racemate can be separated into its enantiomers by the method described above. C24H22F3N303S (489.52), MS (ESI): 490.1 (M + H +). 144

Example 16 3- (2-Cyclopropyl-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [1,2,4- ] oxadiazol-5-one

According to the method described for 3- (2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-Cyclopropyl-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl ) -4H- [1,2,4] oxadiazol-5-one from 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol and 2- -Cyclopropyl-4-fluoro-benzonitrile. The racemate can be separated into its enantiomers by the method described above. C25H22F3N303S (501.53), MS (ESI): 502.1 (M + H +). 145

Example 17 3- (4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -naphthalen-1-yl) -4H- [1,2,4- ] oxadiazol-5-one

According to the method described for 3- (2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -naphthalen-1-yl ) -4H- [1,2,4] oxadiazol-5-one was prepared from 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan- Cyano-4-fluoronaphthalene. The racemate can be separated into its enantiomers by the method described above. C 26 H 20 F 3 N 3 O 3 S (511.53), MS (ESI): 512.2 (M + H +). 146

Example 18 3- (4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2-trifluoromethylphenyl) -4H- [1,2,4] oxadiazole -5-one

According to the method described for 3- (2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2-trifluoromethyl-phenyl ) -4H- [1,2,4] oxadiazol-5-one was prepared from 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol and 4 -fluoro-2- (trifluoromethyl) benzonitrile. The racemate can be separated into its enantiomers by the method described above. C23 H17 F6 N3 O3 S (529.46), MS (ESI): 530.1 (M + H +). 147

Example 19 3- (4'-Fluoro-5- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -biphenyl-2-yl) -4H- [ 1,2,4] oxadiazol-5-one

According to the method described for 3- (2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (4'-Fluoro-5- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} biphenyl-2-yl) -4H- [1,2,4] oxadiazol-5-one from 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan- 1-ol and 5,4'-Difluoro-biphenyl-2-carbonitrile. The racemate can be separated into its enantiomers by the method described above. C28 H21 F4 N3 O3 S (555.56), MS (ESI): 556.1 (M + H +). 148

Example 20 3- (2-Chloro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} -phenyl) - 4H- [1,2,4] oxadiazol-5-one

According to the method described for 3- (2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-chloro-4- (2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5 -yl] -ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one from 2,2,2-

Trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol and 2-Chloro-4-fluoro-benzonitrile. The racemate can be separated into its enantiomers by the method described above. C21 H12 ClF6 N3 O3 S (535.86), MS (ESI): 536.1 (M + H +). 149

Example 21 3- (2-Chloro-4- (2,2-difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -butoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one

F

According to the method described for 3- (2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-chloro-4- {2,2-difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl ] -butoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one was prepared from 2,2-Difluoro-1- [4-methyl-2- (4-trifluoromethylphenyl) yl] -butan-1-ol and 2-Chloro-4-fluoro-benzonitrile. The racemate can be separated into its enantiomers by the method described above. C 23 H 17 ClF 5 N 3 O 3 S (545, 92), MS (ESI): 546.1 (M + H +).

The following examples were prepared according to procedure C: 150

Example 22 3- (2-Fluoro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) - 4H- [1,2,4] oxadiazol-5-one

2-Fluoro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -benzonitrile

1.30 g of 2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol and 815 mg of 4-Bromomethyl-2- fluoro-benzonitrile in 40 ml of dimethylformamide. 192 mg of sodium hydride were added and the mixture stirred at room temperature for one hour. Thereafter, 15 ml of water were added and the mixture extracted three times with 50 ml portions of ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed in vacuo. The residue was purified by reverse phase HPLC to obtain 840 mg of 2-Fluoro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5- yl] -ethoxymethyl} -benzonitrile as an oil. C21H13F7N20S (474.40), MS (ESI): 475.1 (M + H +), Rf (n-heptane: ethyl acetate = 1: 1) = 0.57. 3- (2-Fluoro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one

According to the method described for 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-Fluoro-4- (2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5 -yl] -ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one was prepared from 2-Fluoro-4- (2,2,2-trifluoro-1- [4-methyl-2- - (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -benzonitrile. The racemate was separated into its enantiomers by chiral phase chromatography (Chiralpak AD-H / 39) eluting with n-heptane: iso-propanol: ethanol - 8: 1: 1, Rt-8.13 min and 11.09 min. C22 H14 F7 N3 O3 S (533.43), MS (ESI): 534.1 (M + H +), Rf (n-heptane: ethyl acetate = 1: 1) = 0.14.

Example 23 3- (2-Chloro-4- (2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) - 4H- [1,2,4] oxadiazol-5-one

According to the method described for 3- (2-Fluoro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl } -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- (2,2,2-trifluoro-1- [4-methyl-2- 4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one from 2,2,2-Trifluoro-1- [4- methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol and 4-bromomethyl-2-chlorobenzonitrile. The racemate can be separated into its enantiomers by the method described above. C22 H14 ClF6 N3 O3 S (549.88), MS (ESI): 550.0 (M + H +). 153

Example 24 3- (2-Cyclopropyl-4- (2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) - 4H- [1,2,4] oxadiazol-5-one

2-Bromo-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -benzonitrile

According to the method described for 2-Fluoro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -benzonitrile, 2-Bromo-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -benzonitrile was obtained from 2.2 , 2-Trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol and 2-Bromo-4-bromomethyl-benzonitrile. C21 H13 BrF6 N2 O5 S (535.3), MS (ESI): 335.0 (M + H +), Rf (n-heptane: ethyl acetate = 4: 1) = 0.10. 2-Cyclopropyl-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -benzonitrile

147 mg of 2-Bromo-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -benzonitrile, 147 mg mg of Tricyclohexylphosphine, 71 mg of cyclopropylboronic acid and 224 mg of tripotassium phosphate monohydrate in a mixture of 2 mL of toluene and 0.2 mL of water. The reaction mixture was degassed and 62 mg of palladium (II) acetate was added and the reaction mixture heated under microwave irradiation at 100 ° C for 2.5 hours. The cooled reaction mixture was diluted by the addition of 50 mL of ethyl acetate and filtered. The filtrate was evaporated and the residue purified by reverse phase HPLC to obtain 97 mg of 2-Cyclopropyl-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) - thiazol-5-yl] -ethoxymethyl} -benzonitrile as an oil. C24H18F6N20S (496.48), MS (ESI): 497.2 (M + H +), Rf (n-heptane: ethyl acetate = 4: 1) = 0.16. 155 3- (2-Cyclopropyl-4- (2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one

F

According to the method described for 3- (2-Chloro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl ) -phenyl) -4H- [1,2,4] oxadiazol-5-one, 3- (2-Cyclopropyl-4- {2,2,2-trifluoro-1- [4-methyl-2- 4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one from 2-Cyclopropyl-4- {2,2,2- trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -benzonitrile. The racemate can be separated into its enantiomers by the method described above. C25 H19 F6 N3 O3 S (555.50), MS (ESI): 556.1 (M + H +). 156

Example 25 3- (8- {2,2,2-Trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -quinolin-5-yl) 4H- [1,2,4] oxadiazol-5-one

According to the method described for 3- (2-chloro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl } -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (8- {2,2,2-Trifluoro-1- [4-methyl-2- (4-trifluoromethyl- 5-yl] -ethoxymethyl} -quinolin-5-yl) -4H- [1,2,4] oxadiazol-5-one from 2,2,2-Trifluoro-1- [4- methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol and 8-bromomethyl-quinoline-5-carbonitrile. The racemate can be separated into its enantiomers by the method described above. C25H16F6N403S (566.49), MS (ESI): 567.1 (M + H +). 157

Example 26 3- (4- {2,2,2-Trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -naphthalen-1-yl) - 4H- [1,2,4] oxadiazol-5-one

According to the method described for 3- (2-chloro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl } -phenyl) -4H- [1,2,4] oxadiazol-5-one, 3- (4- {2,2,2-Trifluoro-1- [4-methyl-2- (4-trifluoromethyl- 5-yl] -ethoxymethyl} -naphthalen-1-yl) -4H- [1,2,4] oxadiazol-5-one from 2,2,2-Trifluoro-1- [4- methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol and 5-bromomethyl-naphthalene-1-carbonitrile. The racemate can be separated into its enantiomers by the method described above. C26 H17 F6 N3 O3 S (565.50), MS (ESI): 566.0 (M + H +). 158

Example 27 3- (2-Chloro-6- (2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -pyridin-3 -yl) -4H- [1,2,4] oxadiazol-5-one

F

According to the method described for 3- (2-Chloro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl ) -phenyl) -4H- [1,2,4] oxadiazol-5-one, 3- (2-Chloro-6- (2,2,2-trifluoro-1- [4-methyl- 4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -pyridin-3-yl) -4H- [1,2,4] oxadiazol-5-one from 2,2,2-Trifluoro-1 - [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol and 6-bromomethyl-2-chloro-nicotinonitrile. The racemate can be separated into its enantiomers by the method described above. C21 H13 ClF6 N4 O3 S (550.87), MS (ESI): 551.3 (M + H +). 159

Example 28 3- (2-Fluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxymethyl} -phenyl) -4H- [1,2,4- ] oxadiazol-5-one

According to the method described for 3- (2-Chloro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl } -phenyl) -4H- [1,2,4] oxadiazol-5-one, 3- (2-Fluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole Yl] -propoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one from 1- [4-Methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propan-1-ol and 4-Bromomethyl-2-fluoro-benzonitrile. The racemate can be separated into its enantiomers by the method described above. C23 H19 F4 N3 O3 S (493.48), MS (ESI): 494.2 (M + H +). 160

Example 29 3- (4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxymethyl} -naphthalen-1-yl) -4H- [1,2,4- ] oxadiazol-5-one

According to the method described for 3- (2-Chloro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl } -phenyl) -4H- [1,2,4] oxadiazol-5-one, 3- (4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl ] -propoxymethyl} -naphthalen-1-yl) -4H- [1,2,4] oxadiazol-5-one from 1- [4-Methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propan-1-ol and 5-bromomethyl-naphthalene-1-carbonitrile. The racemate can be separated into its enantiomers by the method described above. C27 H22 F3 N3 O3 S (525.55), MS (ESI): 526.1 (M + H +). 161

EXAMPLE 30 Ethyl 3- (4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-propoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5 -one

(2,2,2-I] - obtained from 1-ol and gt;

According to the method described for 3- (2-chloro-4-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-ixethoxymethyl} -phenyl) -4H- [1 , 2,4] oxadiazol-5-one was 3- (4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one to part: commercially available 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-4-bromomethyl-benzonitrile. The racemate can be separated into its enantiomeric method described above. C 23 H 20 F 3 N 3 O 3 S (475, 49), MS (ESI): 476, 1.1 (M + H +). 162

Example 31 3- (4- (2,2-Difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -butoxymethyl} -phenyl) -4H- [1,2 , 4] oxadiazol-5-one

According to the method described for 3- (2-Chloro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl ) -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (4- (2,2-Difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) 5-yl] -butoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one was prepared from 2,2-Difluoro-1- [4-methyl-2- (4-trifluoromethyl) The title compound can be separated into its enantiomers by the method described above: C 24 H 20 F 5 N 3 O 3 S (525.50), MS (ESI): 526.0 (M + H +).

Example 32 3- (4- {2-Cyclopropyl-2,2-difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one

According to the method described for 3- (2-Chloro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl ) -phenyl) -4H- [1,2,4] oxadiazol-5-one, 3- (4- {2-Cyclopropyl-2,2-difluoro-1- [4-methyl- trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one was prepared from 2-Cyclopropyl-2,2-difluoro-1- [4- methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol and commercially available 4-bromomethylbenzonitrile. The racemate can be separated into its enantiomers by the method described above. C25 H20 F5 N3 O3 S (537.51), MS (ESI): 538.0 (M + H +). 164

Example 33 3- (4- {2- (4-Difluoromethyl-phenyl) -2,2-difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one

According to the method described for 3- (2-Chloro-4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl } -phenyl) -4H- [1,2,4] oxadiazol-5-one, 3- (4- {2- (4-Difluoromethyl-phenyl) -2,2-difluoro-1- [4- (4-trifluoromethyl-phenyl) -2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one from 2- (4- -2-difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethanol and commercially available 4-bromomethyl benzonitrile. The racemate can be separated into its enantiomers by the method described above. C29 H20 F7 N3 O3 S (623.55), MS (ESI): 624.4 (M + H +).

The following examples were prepared according to process K: 165

Example 34 3- (2-Fluoro-4- {2- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -hexyl} -phenyl) -4H- [1,2,4- ] oxadiazol-5-one

16 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -pentan-1-one

1.50 g of 1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -pentan-1-ol in 30 ml of dichloromethane was dissolved. 5.46 g of manganese (IV) oxide (activated on charcoal) was added and the resulting mixture was heated under reflux for 2.5 hours. The cooled reaction mixture was filtered through a pad of celite. The filtrate was evaporated in vacuo to give 1.2 g of 1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -pentan-1-one as an oil. C16 H16 F3 NOS (327.37), MS (ESI): 328.1 (M + H +). (4-Cyano-3-fluoro-benzyl) -phosphonic acid diethyl ester

2.2 g of 4-bromomethyl-2-fluoro-benzonitrile were dissolved in 2.0 ml of triethyl phosphite and stirred at 150 ° C for four hours. Then the triethyl phosphite 167 was removed in vacuo to give 2.5 g of (4-cyano-3-fluoro-benzyl) -phosphonic acid diethyl ester as an oil. C12 H15 FNO3 P (271.23), MS (ESI): 272.1 (M + H +). 2-Fluoro-4 - {(E) -2- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -hex-1-enyl} -benzonitrile

F F

1.0 g of (4-cyano-3-fluoro-benzyl) -phosphonic acid diethyl ester was dissolved in 50 ml of tetrahydrofuran and cooled in an ice bath. At 0 ° C, 103 mg of sodium hydride were added and the mixture stirred for fifteen minutes. 1.2 g of 1- [4-Methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -pentan-1-one, dissolved in 20 ml of tetrahydrofuran, . The cooling bath was removed and the reaction stirred at room temperature for two hours. Then 1.0 g of (4-Cyano-3-fluoro-benzyl) -phosphonic acid diethyl ester and 103 mg of sodium hydride were added and the reaction mixture stirred for another hour. Then, 20 mL of water was added and the mixture extracted five times with 25 mL portions of ethyl acetate. The combined organic layers were dried over MgSO4, then the solvent was removed in vacuo to give 1.6 g of 2-Fluoro-4 - {(E) -2- [4-methyl-2- (4-trifluoromethyl-phenyl ) -thiazol-5-yl] -hex-1-enyl} -benzonitrile as a yellow oil. 168 C 24 H 20 F 4 N 2 S (444.50), MS (ESI): 445.1 (M + H +), Rf (n-heptane: ethyl acetate = 1: 1) = 0.65. 2-Fluoro-4- {2- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -hexyl} -benzonitrile

F

1.6 g of 2-fluoro-4 - {(E) -2- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -hex-1-enyl} -benzonitrile in a mixture of 10 mL of methanol and 10 mL of ethyl acetate. 300 mg of palladium (5% on charcoal) was added and the mixture stirred at room temperature under an atmosphere of hydrogen. After three hours the catalyst was filtered through a pad of celite and the filtrate evaporated in vacuo. The residue was purified by reverse phase HPLC to obtain 1.2 g of 2-Fluoro-4- {2- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -hexyl} - benzonitrile as a lyophilisate. C24H22F4N2S (446.51), MS (ESI): 447.2 (M + H +). 169 3- (2-Fluoro-4- {2- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -hexyl) -phenyl) -4H- [1,2,4] oxadiazole -5-one

F F

1. NH20H, NEt3 2. phenyl chloroformate, j: 3. DBU, MeCN F

F F

, or F Ύ

According to the method described for 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [ 2,4] oxadiazol-5-one, 3- (2-Fluoro-4- {2- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -hexyl} -phenyl ) -4H- [1,2,4] oxadiazol-5-one was prepared from 2-Fluoro-4- {2- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] - hexyl} -benzonitrile. The racemate can be separated into its enantiomers by the method described above. C25 H23 F4 N3 O2 S (505.54), MS (ESI): 506.1 (M + H +). 170

The following examples were prepared according to process A:

Example 35 3- (2-Fluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4- oxadiazol-5-one

F

According to the method described for 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, 3- (2-fluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl ) -4H-1,2,4-oxadiazol-5-one was prepared from 1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan- fluoro-4-hydroxybenzonitrile. C 22 H 17 F 4 N 3 O 3 S (479.46), MS (ESI): 480.0 (M + H +). The racemate was separated into its enantiomers by chiral phase supercritical fluid chromatography (Chiralpak AD, column 350x50 mm, 20 pm) with 25% methanol / 75% carbon dioxide as eluent (120 bar, flow rate: 230 mL / min , UV 230 nm). The enantiomeric excess of each enantiomer was determined by chiral phase analytical supercritical fluid chromatography (Chiralpak AD, 250x4.6 mm column, 20 μm) with 10% methanol / 90% carbon dioxide as eluent (100 bar, flow : 3 mL / min, UV 230 nm): levorotatory enantiomer: > 99% ee, Rt = 5.22 min; dextrorotatory enantiomer: > 99% ee, Rt = 6.81 min.

Example 36 (+) - 3- (2-Fluoro-4 - {(R) -1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazole-5 -yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one

According to the method described for 3- (2-chloro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [ 2,4-oxadiazol-5-one, there was obtained (±) -3- (2-fluoro-4 - {(R) -1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl- piperidin-1-ylmethyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one from (S) -1- [2- (4-trifluoromethyl 4-yl) -propen-1-ol and 2-fluoro-4-hydroxybenzonitrile. C28 H25 F7 N4 O3 S (630.59), MS (ESI): 631.2 (M + H +). 172

The following examples were prepared according to process B:

Example 37 3- (2-Difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4- oxadiazol-5-one

F

0 ° C - * - 60 ° C MN

M / V 150 'C 2-Difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -benzonitrile

To a solution of 1.7 g of 1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol in 4.7 mL of dimethylformamide at 173øC was added 250 mg of a suspension of 55% sodium hydride in mineral oil. The volume reaction was quenched with dimethylformamide to about 8.5 mL. The reaction mixture was stirred for 30 minutes at 5 ° C. 4.3 ml of the resultant mixture was slowly added to a solution of 450 mg of 2-difluoromethoxy-4-fluoro-benzonitrile in 2 ml of dimethylformamide at 5 ° C. The resulting mixture was stirred at 5 ° C allowing the temperature to warm to room temperature. It was then heated in a sealed tube at 60 ° C under microwave irradiation for 15 minutes. After being allowed to cool to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient from heptane 100 to heptane 50 / ethyl acetate 50) to give 490 mg of 2-difluoromethoxy-4- {1- [4-methyl-2- (4 -trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -benzonitrile. C 22 H 17 F 5 N 2 O 5 S (468.45), MS (ESI): (M + H +) 469.0 (M + H +). 174 2-Difluoromethoxy-N-hydroxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -benzamidine

F

F

O ^ F F

NH2 OH

A solution of 485 mg of 2-difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -benzonitrile in 10 mL of methanol were added added 4.166 ml of triethylamine followed by 316 mg of hydroxylamine hydrochloride. The resulting mixture was heated in a sealed tube at 140 ° C under microwave irradiation for 30 minutes. After being allowed to cool to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient from heptane 100 to heptane 60 / ethyl acetate 40) to give 320 mg of 2-difluoromethoxy-N-hydroxy-4- {1- [4-methyl -2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -benzamidine. C22 H20 F5 N3 O3 S (501.48), MS (ESI): 502.0 (M + H +). 3- (2-Difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazole -5-one

To a solution of 315 mg of 2-difluoromethoxy-N-hydroxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -benzamidine in 31% ml of tetrahydrofuran at 0 ° C was added 1.5 mL of N, N-diisopropylethylamine followed by 0.08 mL of phenyl chloroformate. The resulting mixture was stirred for 5 minutes at 0 ° C, then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 6.5 mL of tetrahydrofuran and 0.3 mL of N, N-diisopropylethylamine. The resulting solution was heated in a sealed tube at 150 ° C under microwave irradiation for 15 minutes. After being allowed to cool to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (diisopropyl ether 100, followed by a gradient of dichloromethane 100 to dichloromethane 90 / methanol 10) to give 31 mg of 3- (2-difluoromethoxy-4- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one. C23 H18 F5 N3 O4 S (527, 47), MS (ESI): 528.0 (M + H +). The racemate was separated into its enantiomers by chiral phase supercritical fluid chromatography (Chiralpak AD, column 350x50 mm, 20 pm) with 25% methanol / 75% carbon dioxide as eluent (108 bar, flow rate: 200 mL / min, UV 254 nm). The enantiomeric excess of each enantiomer was determined by chiral phase analytical supercritical fluid chromatography (Chiralpak AD, column 250x4.6 mm, 5 pm) with 20% methanol / 80% carbon dioxide as eluent (100 bar, flow rate: 3 mL / min, UV 220 nm): levorotatory enantiomer: > 99% ee, R t = 3.20 min; dextrorotatory enantiomer: > 99% ee, R t = 6.30 min.

Example 38 3- (2-Methoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4- oxadiazol-5-one

According to the method described for 3- (2-difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1 , 2-methoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -benzamide phenyl) -4H-1,2,4-oxadiazol-5-one from 1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol and 4 -fluoro-2-methoxybenzonitrile. C 23 H 20 F 3 N 3 O 4 S (491, 49), MS (ESI): 492 (M + H +). The racemate was separated into its enantiomers by chiral phase HPLC (Chiralcel OJ-H, column 210x20 mm, 5 pm) with 30% ethanol / 70% heptane as eluent (flow rate: 25 mL / min, UV 254 nm) . the enantiomeric excess of each enantiomer was determined by chiral phase analytical HPLC (Chiralcel OJ-H, 250x4.6mm column, 5pm) with 30% ethanol / 70% heptane as eluent (flow rate: 1mL / min, UV 254 nm): levorotatory enantiomer: > 99% ee, R t = 8.06 min; dextrorotatory enantiomer: > 99% ee, R t = 11.66 min. (+) - 3- (2-Methoxy-4 - {(R) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- 1,2,4-oxadiazol-5-one

According to the method described for 3- (2-difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1 , 2-methoxy-4 - {(R) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol- 5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one from (+) - (R) -1- [4-methyl-2- (4-trifluoromethyl-phenyl ) -thiazol-5-yl] -propan-1-ol and 4-fluoro-2-methoxybenzonitrile. C 23 H 20 F 3 N 3 O 4 S (491.49), MS (ESI): 492.1 (M + H +). The enantiomeric excess of this dextrorotatory enantiomer was determined by chiral phase analytical HPLC (Chiralcel OJ-H, column 250x4.6mm, 5æm) with 30% ethanol / 70% heptane as eluant (flow rate: 1mL / min, UV 254 nm) by comparison to the racemic mixture: ee 96%, R t = 10.43 min.

Example 39 3- (2-Hydroxy-4- (1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy) -phenyl) -4H-1,2,4- oxadiazol-5-one

A stirred solution of 136 mg of 3- (2-methoxy-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -phenyl) - 4H-1,2,4-oxadiazol-5-one in 5 mL of dichloromethane at -70 ° C was added 0.6 mL of a 1M solution of boron tribromide in dichloromethane. After 1 h at -60 ° C, the reaction mixture was poured into methanol and a saturated aqueous NaHCO 3 solution, then extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol gradient from 100/0 to 90/10) to give 22 mg of 3- (2-hydroxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one. C22 H18 F3 N3 O4 S (477, 47), MS (ESI): 478 (M + H +). 179

Example 40 3- (5-Fluoro-2-methoxy-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- 2,4-oxadiazol-5-one

According to the method described for 3- (2-difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1 , 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -piperidine- 1-yl) propanoyl} -4H-1,2,4-oxadiazol-5-one from 1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propan-1-ol and commercially available 4,5-difluoro-2-methoxybenzonitrile. C23 H19 F4 N3 O4 S (509, 48), MS (ESI): 509.9 (M + H +). The racemate was separated into its enantiomers by chiral phase supercritical fluid chromatography (Chiralpak OJ, column 250x21 mm, 5 pm) with 15% methanol / 85% carbon dioxide as eluant (flow rate: 90 mL / min, UV 210 nm ). The enantiomeric excess of each enantiomer was determined by chiral phase analytical supercritical fluid chromatography (Chiralpak OJ, column 250x4, 6 mm, 10 pm) with 10% methanol / 90% carbon dioxide as eluent (100 bar, flow rate: 3 mL / min, UV 210 nm): levorotatory enantiomer: > 99% ee, R t = 8.67 min; dextrorotatory enantiomer: > 99% ee, R t = 11.42 min. (+) - 3- (5-Fluoro-2-methoxy-4 - {(R) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl ) -4H-1,2,4-oxadiazol-5-one

/

According to the method described for 3- (2-difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1 , 5-fluoro-2-methoxy-4 - {(R) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) ) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one from (+) - (R) -1- [4-methyl-2- trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol and 4,5-difluoro-2-methoxybenzonitrile. C23 H19 F4 N3 O4 S (509.48), MS (ESI): 510.0 (M + H +). The enantiomeric excess of this dextrorotatory enantiomer was determined by chiral phase analytical HPLC (Chiralcel OJ-H, column 250x4.6mm, 5æm) with 30% ethanol / 70% heptane as eluent (flow rate: 1mL / min, UV 254 nm) by comparison with the racemic mixture: ee 96%, R t = 8.63 min. 181

Example 41 (+) - 3- (2-Difluoromethoxy-5-fluoro-4 (R) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazot-5-yl] -propoxy} phenyl) -4H-1,2,4-oxadiazol-5-one

F

According to the method described for 3- (2-difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1 , 2,4-oxadiazol-5-one, (+) - 3- (2-difluoromethoxy-5-fluoro-4 - {(R) -1- [4-methyl-2- (4-trifluoromethyl-phenyl ) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one from (+) - (R) -1- [4-methyl-2- trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol and 2-difluoromethoxy-4,5-difluoro-benzonitrile. C23 H17 F6 N3 O4 S (545, 46), MS (ESI): 546.0 (M + H +). 182

Example 42 3- (2-Methoxy-4- {1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propoxy} -4H-1,2,4-oxadiazol-5-one

According to the method described for 3- (2-difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1 , 2-methoxy-4- {1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) - thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one was prepared from 1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin- yl] -ethyl] -thiazol-5-yl] -propan-1-ol and 4-fluoro-2-methoxy-benzonitrile. C29H28F6N40S (642, 63), MS (ESI): 643.2 (M + H +). The racemate was separated into its enantiomers by chiral phase supercritical fluid chromatography (Chiralpak AD, 250x50 mm column, 20 pm) with 35% methanol / 65% carbon dioxide as eluent (70 bar, 30øC, flow rate: 250 mL / min, UV 254 nm). The enantiomeric excess of each enantiomer was determined by chiral phase analytical supercritical fluid chromatography (Chiralpak AD, 250x4.6 mm column, 10 pm) with 35% methanol / 65% carbon dioxide as eluent (100 bar, flow : 3 mL / min, UV 254 nm): levorotatory enantiomer: > 99% ee, R t = 2.7 min; dextrorotatory enantiomer: > 99% ee, R t = 5.7 min.

Example 43 3- (5-Fluoro-2-methoxy-4- {1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] - propoxy-phenyl) -4H-1,2,4-oxadiazol-5-one

According to the method described for 3- (2-difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1 , 2,4-oxadiazol-5-one, 3- (5-fluoro-2-methoxy-4- {1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1 5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one was prepared from 1- [2- (4-trifluoromethyl-phenyl) -4- (4- 1-ylmethyl) -thiazol-5-yl] -propan-1-ol and commercially available 4,5-difluoro-2-methoxy-benzonitrile. C29 H27 F7 N4 O4 S (660.62), MS (ESI): 661.0 (M + H +). The racemate was separated into its enantiomers by chiral phase supercritical fluid chromatography (Chiralpak AD, 250 x 50 mm column, 20 μm) with 10% methanol / 90% carbon dioxide as eluent (140 bar, flow rate: 250 mL / min, UV 254 nm). The enantiomeric excess of each enantiomer was determined by chiral phase analytical supercritical fluid chromatography (Chiralpak AD, 250x4.6 mm column, 20 pm) with 10% methanol / 90% carbon dioxide as eluent (100 bar, flow rate: 3 mL / min, UV 254 nm): levorotatory enantiomer: > 99% ee, R t = 11.89 min; dextrorotatory enantiomer: > 99% ee, Rt = 16.92 min.

Example 44 3- (2- (2,2,2-Trifluoro-ethoxy) -4- {1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazole -5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one

According to the method described for 3- (2-difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} phenyl) -4H- 2,4-oxadiazol-5-one, 3- (2- (2,2,2-trifluoro-ethoxy) -4- {1- [2- (4-trifluoromethylphenyl) -4- (4- trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propoxy} -phenyl) -4Η-1,2,4-oxadiazol-5-one from 1- [2- (4-trifluoromethyl) phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propan-1-ol and 4-fluoro-2- (2,2,2-trifluoro-ethoxy) -benzonitrile . C 30 H 27 F 9 N 4 O 4 S (710.62), MS (ESI): 712.1 (M + H +). The racemate was separated into its enantiomers by chiral phase supercritical fluid chromatography (Chiralpak AD-H, column 20 mm diameter, 5 pm) with 15% methanol / 85% carbon dioxide as eluent (70 bar, 30øC , flow rate: 100 mL / min, UV 254 nm). The enantiomeric excess of each enantiomer was determined by chiral phase analytical supercritical fluid chromatography (Chiralpak AD-H, 250x4.6 mm column, 5 pm) with 15% methanol / 85% carbon dioxide as the eluent (100 bar, flow rate: 3 mL / min, UV 254 nm): first enantiomer: > 99% ee, R t = 2.85 min; second enantiomer: > 99% ee, R t = 5.74 min. 186

Example 45 3- (2-Difluoromethoxy-4- {1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propoxy} -phenyl ) -4H-1,2,4-oxadiazol-5-one

According to the method described for 3- (2-difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1 , 2,4-oxadiazol-5-one, 3- (2-difluoromethoxy-4- {1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) - thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one was prepared from 1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin- yl] -ethyl] -thiazol-5-yl] -propan-1-ol and 2-difluoromethoxy-4-fluoro-benzonitrile. C29 H26 F8 N4 O4 S (678.61), MS (ESI): 680.4 (M + H +). The racemate was separated into its enantiomers by chiral phase supercritical fluid chromatography (Chiralpak AD, 250x50 mm column, 20 μm) with 20% acetonitrile / 80% carbon dioxide as eluent (105 bar, flow rate: 200 mL / min, UV 254 nm). The enantiomeric excess of each enantiomer was determined by chiral phase analytical supercritical fluid chromatography (Chiralpak AD-H, 250x4.6 mm column, 5 μm) with 15% methanol / 85% carbon dioxide as the eluent (100 bar , flow rate: 3 mL / min, UV 254 nm): levorotatory enantiomer: > 99% ee, R t = 3.14 min; dextrorotatory enantiomer: > 99% ee, Rt = 5.34 min. (+) - 3- (2-Difluoromethoxy-4 - {(R) -1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl ] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one

According to the method described for 3- (2-difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1 (Except for the step of adding hydroxylamine which was performed under microwave irradiation at 100 ° C for 2 h), there was obtained (+) - 3- (2-difluoromethoxy-4- {(R) -1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2 , 4-oxadiazol-5-one from (R) -1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propan- 1-ol and 2-difluoromethoxy-4-fluoro-benzonitrile. C29 H26 F8 N4 O4 S (678.61), MS (ESI): 679.3 (M + H +).

Example 46 3- (2-Difluoromethoxy-5-fluoro-4- {1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] - propoxy-phenyl) -4H-1,2,4-oxadiazol-5-one

According to the method described for 3- (2-difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1 , 2,4-oxadiazol-5-one, 3- (2-difluoromethoxy-5-fluoro-4- {1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1 5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one was prepared from 1- [2- (4-trifluoromethyl-phenyl) -4- (4- trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propan-1-ol and 2-difluoromethoxy-4,5-difluoro-benzonitrile. C29 H25 F9 N4 O4 S (696.60), MS (ESI): 698.5 (M + H +). The racemate was separated into its enantiomers by chiral phase supercritical fluid chromatography (Chiralpak AD-H, 250 x 50 mm column, 5 μm) with 5% methanol / 95% carbon dioxide as eluent (129 bar, flow rate: 100 mL / min, UV 254 nm). The enantiomeric excess of each enantiomer was determined by chiral phase analytical supercritical fluid chromatography (Chiralpak AD-H, 250x4.6 mm column, 5 μm) with 5% methanol / 95% carbon dioxide as the eluent (100 bar , flow rate: 3 mL / min, UV 254 nm): levorotatory enantiomer: > 99% ee, R t = 10.1 min; dextrorotatory enantiomer: > 99% ee, R t = 15.5 min.

The following examples were prepared according to process J:

Example 47 3- [5-Fluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2- ethoxy) -phenyl] -4H-1,2,4-oxadiazol-5-one

OH KOtBu

F F

CN KOtBu

CF.CH.OH

-60X

NEt, MW 140'C

2) iPr2NEt MW, 150 2.5-Difluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -benzonitrile

A solution of 900 mg of 1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol in 2 mL of tetrahydrofuran at 5 ° C 3.3 ml of a molar solution of potassium tert-butoxide in tert-butanol were slowly added. After stirring at 5 ° C for 30 minutes, the resulting solution was slowly added to a solution of 469 mg of 2,4,5-trifluorobenzonitrile in 2 ml of tetrahydrofuran at -60 ° C. The resulting mixture was stirred for 1 h at -60 ° C, then stirred overnight, allowing the temperature to warm to room temperature. It was then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient from heptane 100 to heptane 80 / ethyl acetate 20) to give 1.25 g of 2,5-difluoro-4- {1- [4-methyl- 2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -benzonitrile. C 21 H 15 F 5 N 2 O 4 S (438, 42), MS (ESI): 439.0 (M + H +). 191 5-Fluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2-trifluoro-ethoxy) -benzonitrile

To a solution of 342 mg of trifluoroethanol in 2.1 ml of tetrahydrofuran at 5øC were slowly added 4 ml of a molar solution of potassium tert-butoxide in tert -butanol. After stirring at 5 ° C for 30 minutes, the resulting solution was slowly added to a solution of 1.25 g of 2,5-difluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl ) -thiazol-5-yl] -propoxy} -benzonitrile in 5.6 mL of tetrahydrofuran at -60 ° C. The resulting mixture was stirred overnight allowing the temperature to warm to room temperature. It was then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient from heptane 100 to heptane 70 / ethyl acetate 30) to give 1.09 g of 5-fluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2-trifluoro-ethoxy) -benzonitrile. C23 H17 F7 N2 O2 S (518.45), MS (ESI): 519.0 (M + H +). 192 - [5-Fluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,2-trifluoro-ethoxy) phenyl] -4H-1,2,4-oxadiazol-5-one

140 * C

According to the method described for 3- (2-difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1 , 5-fluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} 2- (2,2,2-trifluoro-ethoxy) -phenyl] -4H-1,2,4-oxadiazol-5-one from 5-fluoro-4- {1- [4-methyl-2- 4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2-trifluoro-ethoxy) -benzonitrile. C24H18F7N304S (577, 48), MS (ESI): 578.0 (M + H +). The racemate was separated into its enantiomers by chiral phase supercritical fluid chromatography (Chiralpak AD, column 350x50 mm, 20 pm) with 15% methanol / 85% carbon dioxide as eluent (123 bar, flow rate: 250 mL / min , UV 230 nm). The enantiomeric excess of each enantiomer was determined by chiral phase analytical supercritical fluid chromatography (Chiralpak AD, column 250x4.6 mm, 205 Âμm) with 193 10% methanol / 90% carbon dioxide as eluent (100 bar, flow rate : 3 mL / min, UV 230nm): levorotatory enantiomer: > 99% ee,

R t = 5.22 min; dextrorotatory enantiomer: > 99% ee, Rt = 6.81 min. 3- [5-fluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2-trifluoro-ethoxy ) -phenyl] -4H-1,2,4-oxadiazol-5-one can also be prepared according to the method described for 3- (2-difluoromethoxy-4- {1- [4-methyl- Trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one starting from 1- [4-methyl-2- (4-trifluoromethyl-phenyl) - thiazol-5-yl] -propan-1-ol and 4,5-difluoro-2- (2,2,2-trifluoro-ethoxy) -benzonitrile.

Example 48 3- [4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2-trifluoro-ethoxy) -phenyl ] -4H-1,2,4-oxadiazol-5-one

According to the method described for 3- [5-fluoro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2- -trifluoro-ethoxy) -phenyl] -4H-1,2,4-oxadiazol-5-one, there was obtained W02005 / 111003 194 3- [4- {1- [4-methyl-2- (4-trifluoromethyl- phenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2-trifluoro-ethoxy) -phenyl] -4H-1,2,4-oxadiazol-5-one from 1- [4- 2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol and 2-fluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) - thiazol-5-yl] -propoxy} -benzonitrile which was prepared according to procedure A. C24 H19 F6 N3 O4 S (559, 49), MS (ESI): 560 (M + H +). The racemate was separated into its enantiomers by chiral phase supercritical fluid chromatography (Chiralpak AD, column 250x50 mm, 5 pm) with 25% MeOH and 0.1% triethylamine in carbon dioxide as eluent (130 bar, flow rate: 90 mL / min, UV 205 nm). The enantiomeric excess of each enantiomer was determined by chiral phase analytical supercritical fluid chromatography (Chiralpak AD, column 250x4.6 mm, 5 pm) with 20% MeOH and 0.1% triethylamine in carbon dioxide as eluent (100 bar, flow rate: 3 mL / min, UV 205 nm): levorotatory enantiomer: > 99% ee, Rt 2.94 min; dextrorotatory enantiomer: > 99% ee, R t = 5.11 min. (+) - 3- [4 - {(R) -1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2- trifluoro-ethoxy) -phenyl] -4H-1,2,4-oxadiazol-5-one

Following procedure B according to the method described for 3- (2-difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl ) -4H-1,2,4-oxadiazol-5-one there was obtained (+) - 3- [4 - {(R) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole -5-yl] -propoxy} -2- (2,2,2-trifluoro-ethoxy) -phenyl] -4H-1,2,4-oxadiazol-5-one from (+) - (R) - 1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propan-1-ol and 4-fluoro-2- (2,2,2-trifluoro-ethoxy) -benzonitrile. C24 H19 F6 N3 O4 S (559.49), MS (ESI): 560.1 (M + H +). The enantiomeric excess of this dextrorotatory enantiomer was determined by chiral phase analytical supercritical fluid chromatography (Chiralpak AD, 250x4.6 mm column, 5 μm) with 20% methanol / 80% carbon dioxide as eluent (100 bar, flow rate: 3 mL / min, UV 254 nm) by comparison to the racemic mixture: ee > 99%, R t = 5.49 min. 196

Example 49 3- (5-Fluoro-2- (2,2,2-trifluoro-ethoxy) -4- {1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin- ylmethyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one

According to the method described for 3- [5-fluoro-4- {1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2- trifluoro-ethoxy) -phenyl] -4H-1,2,4-oxadiazol-5-one, there was obtained 3- (5-fluoro-2- (2,2,2-trifluoroethoxy) -4- {1- [ 2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propoxyl} phenyl) -4H-1,2,4-oxadiazol-5-one from 1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propan-1-ol and 2,4,5-trifluorobenzonitrile . C30 H26 F10 N4 O4 S (728.61), MS (ESI): 730.6 (M + H +).

Lisbon, 19 October 2012 197

Claims (15)

Compounds of the series selected from 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- {2-methyl-1- [4-methyl-2- (4-trifluoromethyl-phenyl) thiazol-5-yl] -propoxy phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- {3-methyl-1- [4-methyl-2- (4-trifluoromethylphenyl) thiazole -5-yl] -butoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl- phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- {1- [4-methyl-2- ( 4-trifluoromethyl-phenyl) -thiazol-5-yl] -2-phenyl-ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4 - {[4- 2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -phenylmethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- - {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -3-phenyl-propoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-5-yl] -3-phenyl-propoxy} -phenyl) -4H- [1,2- , 4] oxadiazol-5-one 3- (2-Chloro-4- {2- (4-fluoro-phenyl) -1- 2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro- 4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -2-pyridin-2-yl-ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Bromo-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [ 2,4] oxadiazol-5-one 3- [4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2- 3- (2-Methoxymethyl-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -piperidin-4-yl] thiol-5-yl] -propoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Ethoxymethyl-4- {1- [4-methyl-2- (4-trifluoromethyl 3- (2-Ethyl-4- {1- [4-methyl-2-methyl-2- (4-methylphenyl) -thiazol-5-yl] -thiazol-5-yl] -propoxy} -phenyl) -4H- [1,2,4] oxadiazol- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Cyclopropyl-4- {1- [4- methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (4- {1- [4- Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -naphthalen-1-yl) -4H- [ 1,2,4] oxadiazol-5-one 3- (4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2-trifluoromethylphenyl) -4H - [1,2,4] oxadiazol-5-one 3- (4'-Fluoro-5- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} 2-Chloro-4- (2,2,2-trifluoro-1- [4-methyl-2-oxo-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- (2,2-difluoro-1 - [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -butoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Fluoro- 4- {2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol- 5-yl] -ethoxymethyl} -phenyl) -piperidine-5-carboxylic acid 3- (2-chloro-4- (2,2,2- (2-Cyclopropyl-4- (2,2,2-trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol- 5-yl] -ethoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (8- {2,2,2-Trifluoro-1- [4-methyl-2- (4-trifluoromethyl -phenyl) -thiazol-5-yl] -ethoxymethyl} -quin 3- (4- (2,2,2-Trifluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl] 5-yl] -ethoxymethyl} -naphthalen-1-yl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Fluoro-4- {1- [4- 2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (4- {1- [4-Methyl 2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxymethyl} -naphthalen-1-yl) -4H- [1,2,4] oxadiazol-5-one 3- (4- {1- (4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (4- { 2-Difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -butoxymethyl} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (4- {2-Cyclopropyl-2,2-difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxymethyl} -phenyl) -4H- [1,2- , 4] oxadiazol-5-one 3- (4- {2- (4-Difluoromethyl-phenyl) -2,2-difluoro-1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5 3- (2-Fluoro-4- {2- [4-methyl-2- (4-trifluoromethyl-phenyl) -piperazin- -thiazol-5-yl] -hexyl} -phenyl) -4H- [1,2,4] oxadiaz ol-5-one 3- (2-Fluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2 , 4-oxadiazol-5-one 3- (2-Fluoro-4 - {(R) -1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazole -5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2-Difluoromethoxy-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl 5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2-Methoxy-4- {1- [4- trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2-Methoxy-4 - {(R) -1- [4- 2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2-Hydroxy-4- {1 - [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (5-Fluoro-2- 4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one - (5-Fluoro-2-methoxy-4 - {(R) -1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1 , 4-oxadiazol-5-one 3- (2-Difluoromethoxy-5-fluoro-4 - {(R) -1- [4- 2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2-Methoxy-4- {1 - [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5 2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -amide propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2- (2,2,2-Trifluoro-ethoxy) -4- {1- [2- (4-trifluoromethyl-phenyl ) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2-Difluoromethoxy-4- - {1- [2- (4-Trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4- oxadiazol-5-one 3- (2-Difluoromethoxy-4 - {(R) -1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazole-5 3-yl) propoxy} phenyl) -4H-1,2,4-oxadiazol-5-one 3- (2-Difluoromethoxy-5-fluoro-4- {1- [2- (4-trifluoromethyl-phenyl) - 4- (4-trifluoromethyl-piperidin-1-ylmethyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazo 3- [5-Fluoro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2- 3- [4- {1- [4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -piperidin- ] -propoxy} -2- (2,2,2-trifluoro-ethoxy) -phenyl] -4H-1,2,4-oxadiazol-5-one 3- [4 - {(R) -1- [4- Methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -2- (2,2,2-trifluoro-ethoxy) -phenyl] -4H-1,2,4-oxadiazol-5 -one 3- (5-Fluoro-2- (2,2,2-trifluoro-ethoxy) -4- {1- [2- (4-trifluoromethyl-phenyl) -4- (4-trifluoromethyl-piperidin- ylmethyl) -thiazol-5-yl] -propoxy} -phenyl) -4H-1,2,4-oxadiazol-5-one. Compounds of the series according to claim 1 selected from 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -ethoxy} - phenyl-4- (2-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-4- 5-yl] -propoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- {3-methyl- 5-yl] -butoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- {1- [4-methyl- 2- (4-Trifluoromethyl-phenyl) -thiazol-5-yl] -propoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2-Chloro-4- {1- [ 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -2-phenyl-ethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3- (2- Chloro-4 - {[4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -phenylmethoxy} -phenyl) -4H- [1,2,4] oxadiazol-5-one 3 - (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -thiazol-5-yl] -3-phenyl-propoxy} -phenyl) -4H- [ 4-oxadiazol-5-one 3- (2-Chloro-4- {1- [4-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-5-yl] -3-phenyl-propoxy} -4H- [1,2,4] oxadiazol-5-one. A pharmaceutical product comprising one or more compounds as claimed in claim 1 or 2. A pharmaceutical product comprising one or more compounds as claimed in claim 1 or 2 and one or more active substances which have favorable effects on the metabolic disorders or disorders often associated therewith. 7 A pharmaceutical product comprising one or more compounds as claimed in claim 1 or 2 and one or more antidiabetic agents. A pharmaceutical product comprising one or more compounds as claimed in claim 1 or 2 and one or more lipid modulators. Compounds as claimed in claim 1 or 2 for use in the treatment and / or prevention of disorders of fatty acid metabolism and disorders of use of glucose. Compounds as claimed in claim 1 or 2 for use in the treatment and / or prevention of disorders in which insulin resistance is involved. Compounds as claimed in claim 1 or 2 for use in the treatment and / or prevention of diabetes mellitus including prevention of the sequelae associated therewith. Compounds as claimed in claim 1 or 2 for use in the treatment and / or prevention of dyslipidemias and their sequelae. Compounds as claimed in claim 1 or 2 for use in the treatment and / or prevention of conditions which may be associated with the metabolic syndrome. Compounds as claimed in claim 1 or 2 for use in the treatment and / or prevention of demyelinating disorders and other neurodegenerative disorders of the central and peripheral nervous system. Compounds as claimed in claim 1 or 2 in association with at least one other active compound for use in the treatment of disorders of fatty acid metabolism and disorders of use of glucose. Compounds as claimed in claim 1 or 2 in association with at least one further active compound for use in the treatment of disorders in which insulin resistance is involved. A process for the preparation of a pharmaceutical product comprising one or more of the compounds as claimed in claim 1 or 2, which comprises mixing the active compound with a pharmaceutically suitable carrier and placing this mixture in a form suitable for administration. Lisbon, October 19, 2012 9